U.S. patent application number 10/491231 was filed with the patent office on 2005-02-17 for thiazolyl substituted aminopyrimidines as plant protection agents.
Invention is credited to Eberle, Martin, Lutz, William, Mueller, Urs, Pillonel, Christian, Stanetty, Peter.
Application Number | 20050038059 10/491231 |
Document ID | / |
Family ID | 9923063 |
Filed Date | 2005-02-17 |
United States Patent
Application |
20050038059 |
Kind Code |
A1 |
Mueller, Urs ; et
al. |
February 17, 2005 |
Thiazolyl substituted aminopyrimidines as plant protection
agents
Abstract
Compounds of formula (I), or a salt thereof, wherein R.sub.1,
R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, and R.sub.8
are specified organic redicals; and compositions containing them,
processes for making them and their use as fungicides.
Inventors: |
Mueller, Urs; (Basel,
CH) ; Eberle, Martin; (Basel, CH) ; Pillonel,
Christian; (Basel, CH) ; Lutz, William;
(Basel, CH) ; Stanetty, Peter; (Wien, AT) |
Correspondence
Address: |
SYNGENTA CROP PROTECTION , INC.
PATENT AND TRADEMARK DEPARTMENT
410 SWING ROAD
GREENSBORO
NC
27409
US
|
Family ID: |
9923063 |
Appl. No.: |
10/491231 |
Filed: |
September 24, 2004 |
PCT Filed: |
September 19, 2002 |
PCT NO: |
PCT/IB02/03868 |
Current U.S.
Class: |
514/275 ;
544/331 |
Current CPC
Class: |
A01N 53/00 20130101;
C07D 417/04 20130101; A01N 43/78 20130101; C07D 417/14
20130101 |
Class at
Publication: |
514/275 ;
544/331 |
International
Class: |
A61K 031/506; C07D
417/04 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 1, 2001 |
GB |
0123589.4 |
Claims
1. A N-[2-amino-thiazol-5-yl-pyrimidin-yl]-N-phenyl-amine of the
formula I 289wherein R.sub.1 is hydrogen, C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.3-C.sub.7cycloalkyl-C.sub.1-C.sub.4alkyl,
C.sub.1-C.sub.4alkyl-C.su-
b.3-C.sub.7cycloalkyl-C.sub.1-C.sub.4alkyl,
C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6hydroxyalkyl,
C.sub.1-C.sub.4alkoxy-C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6aminoalkyl,
C.sub.1-C.sub.4alkyl-C.sub.1-C.sub.6aminoalkyl- ,
di(C.sub.1-C.sub.4alkyl)-C.sub.1-C.sub.6aminoalkyl,
aryl-C.sub.1-C.sub.4alkyl, heteroaryl-C.sub.1-C.sub.4alkyl, or a
group --CO--R.sub.9, --CO--OR.sub.10, --CO--NR.sub.10R.sub.11, or
--NR.sub.10R.sub.11; R.sub.2 is hydrogen, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6hydroxyalkyl,
C.sub.1-C.sub.4alkoxy-C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6aminoalkyl,
C.sub.1-C.sub.4alkyl-C.sub.1-C.sub.6aminoalkyl or a group
--CO--R.sub.9; R.sub.1 and R.sub.2 together with the nitrogen to
which they are bound form an optionally substituted N-linked
saturated or unsaturated N-ring system which may contain oxygen or
sulfur as a ring member, or form a group
--N.dbd.CR.sub.9--NR.sub.10R.sub.11; R.sub.3 is hydrogen, halogen
or C.sub.1-C.sub.4alkyl; R.sub.4 is hydrogen, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6cyanoalkyl,
C.sub.3-C.sub.7cycloalkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6haloalkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.2-C.sub.6haloalkynyl, amino, C.sub.1-C.sub.6alkylamino,
di(C.sub.1-C.sub.4alkyl)-amino, halogen, hydroxy, mercapto, cyano,
C.sub.1-C.sub.6alkoxy, C.sub.2-C.sub.6alkenyloxy,
C.sub.2-C.sub.6alkynylo- xy, C.sub.1-C.sub.6haloalkoxy,
C.sub.1-C.sub.8alkanoyloxy-C.sub.1-C.sub.6a- lkyl,
C.sub.1-C.sub.6alkylthio, C.sub.1-C.sub.6alkylsulfinyl,
C.sub.1-C.sub.6alkylsulfonyl, C.sub.1-C.sub.6hydroxyalkyl,
C.sub.1-C.sub.4alkoxy-C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6aminoalkyl,
C.sub.1-C.sub.4alkyl-C.sub.1-C.sub.6aminoalkyl,
di(C.sub.1-C.sub.4alkyl)-- C.sub.1-C.sub.6aminoalkyl,
C.sub.1-C.sub.8alkoxycarbonyl,
C.sub.1-C.sub.8alkanoyl-C.sub.1-C.sub.6aminoalkyl, optionally
substituted heterocyclyl, optionally substituted aryl, optionally
substituted heteroaryl, or a group --CO--R.sub.9, --O--CO--R.sub.9,
--NH--CO--R.sub.9, --(C.sub.1-C.sub.6alkylene-)-CO--R.sub.9,
--C(--O--C.sub.1-C.sub.6alkylene-O--)-R.sub.9,
--C(.dbd.NOR.sub.8)--R.sub- .9 or --CO--NR.sub.10R.sub.11; R.sub.5
is hydrogen, hydroxy, halogen, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkoxy or C.sub.1-C.sub.6haloalkyl; R.sub.6 is
hydrogen, C.sub.1-C.sub.6alkyl or C.sub.1-C.sub.6haloalkyl; R.sub.7
is thienyl , pyridinyl or aryl each optionally substituted with one
to three substituents independently selected from the group
comprising halogen, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4alkoxy,
C.sub.1-C.sub.4haloalkyl and C.sub.1-C.sub.4haloalkoxy; R.sub.8 is
hydrogen, C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.4alkoxy-C.sub.1-C.sub.6alkyl,
or a group --CO--R.sub.9 or --CO--OR.sub.10; R.sub.9 is hydrogen,
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl,
C.sub.3-C.sub.7cycloalkyl- ,
C.sub.3-C.sub.7cycloalkyl-C.sub.1-C.sub.4alkyl, aryl,
C.sub.1-C.sub.4alkyl-C.sub.3-C.sub.7cycloalkyl-C.sub.1-C.sub.4alkyl,
aryl-C.sub.1-C.sub.4alkyl, heteroaryl or
heteroaryl-C.sub.1-C.sub.4alkyl; R.sub.10 is C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6haloalkyl,
C.sub.3-C.sub.7cycloalkyl-C.sub.1-C.sub.4alkyl or
C.sub.1-C.sub.4alkoxy-C- .sub.1-C.sub.6alkyl; R.sub.11 is
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.3-C.sub.7cycloalkyl-C.sub.1-C.sub.4alkyl- ,
C.sub.1-C.sub.4alkoxy-C.sub.1-C.sub.6alkyl, aryl or heteroaryl; or
a salt thereof.
2. A compound according to claim 1, wherein R.sub.3, R.sub.6 and
R.sub.8 are all hydrogen.
3. A compound according to claim 1, wherein R.sub.1 is hydrogen,
C.sub.1-C.sub.4alkyl, or is a group --CO--R.sub.9; and R.sub.2 is
hydrogen or C.sub.1-C.sub.4alkyl; or R.sub.1 and R.sub.2 together
form the group --N.dbd.CR.sub.9--NR.sub.10R.sub.11; R.sub.3 is
hydrogen or methyl; and R.sub.4 is hydrogen, hydroxy, amino,
C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4haloalkyl,
C.sub.1-C.sub.4cyanoalkyl, C.sub.1-C.sub.6alkylamino,
di(C.sub.1-C.sub.4alkyl)-amino, C.sub.1-C.sub.6aminoalkyl, halogen,
mercapto, cyano, C.sub.1-C.sub.6alkoxy, C.sub.2-C.sub.6alkenyloxy,
C.sub.2-C.sub.6alkynylo- xy, C.sub.1-C.sub.6alkylthio,
C.sub.1-C.sub.6alkylsulfinyl, C.sub.1-C.sub.6alkylsulfonyl,
C.sub.1-C.sub.6hydroxyalkyl,
C.sub.1-C.sub.4alkoxy-C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.4alkyl-C.sub.1-- C.sub.6aminoalkyl,
di(C.sub.1-C.sub.4alkyl)-C.sub.1-C.sub.6aminoalkyl,
C.sub.1-C.sub.4alkoxycarbonyl; --CO--R.sub.9, or --NH--CO--R.sub.9;
and R.sub.5 is hydrogen, hydroxy, methoxy or methylthio; and
R.sub.6 is hydrogen or methoxy; and R.sub.7 is 4-pyridyl or
optionally substituted aryl carrying one to three substituents
independently selected from the group comprising halogen,
C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4alkoxy,
C.sub.1-C.sub.4haloalkyl and C.sub.1-C.sub.4haloalkoxy; and R.sub.8
is hydrogen, C.sub.1-C.sub.4alkanoyl, C.sub.1-C.sub.4haloalkanoyl
or C.sub.1-C.sub.4alkyl.
4. A compound according to claim 1, wherein; R.sub.1 is hydrogen,
methyl, trifluoroacetyl, pentafluoropropionyl or
heptafluorobutyryl; and R.sub.2 is hydrogen or
C.sub.1-C.sub.4alkyl; or R.sub.1 and R.sub.2 are both hydrogen or
R.sub.1 and R.sub.2 together form the groups
--N.dbd.CH--N(CH.sub.3).sub.2 or
--N.dbd.C(CH.sub.3)--N(CH.sub.3).sub.2; and R.sub.3 is hydrogen or
methyl; and R.sub.4 is hydrogen, hydroxy, C.sub.1-C.sub.4alkyl,
C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4haloalkoxy,
C.sub.1-C.sub.4haloalkyl, C.sub.1-C.sub.4cyanoalkyl,
C.sub.1-C.sub.4alkanoyloxy, C.sub.1-C.sub.4hydroxyalkyl,
C.sub.1-C.sub.4haloalkanoyloxy,
C.sub.1-C.sub.4alkanoyl-C.sub.1-C.sub.6am- inoalkyl,
C.sub.1-C.sub.4alkanoyloxy-C.sub.1-C.sub.4alkyl,
C.sub.1-C.sub.4alkanoyl, C.sub.1-C.sub.4alkylthio or
C.sub.1-C.sub.4alkoxycarbonyl; and R.sub.5 is hydrogen or hydroxy;
and R.sub.6 is hydrogen; and R.sub.7 is phenyl or halophenyl; and
R.sub.8 is hydrogen or C.sub.1-C.sub.4fluoroalkanoyl.
5. A compound according to claim 1, wherein; R.sub.1 is acetyl; and
R.sub.2 is hydrogen or methyl; or R.sub.1 and R.sub.2 together form
the groups --N=CH--N(CH.sub.3).sub.2 or
--N.dbd.C(CH.sub.3)--N(CH.sub.3).sub.- 2; and R.sub.3 is hydrogen;
and R.sub.4 is hydrogen, hydroxy, cyano, fluorine, chlorine,
bromine, methyl, tert.butyl, methylthio, trifluoromethyl,
hydroxymethyl, cyanomthyl, 2-cyanoethyl, 1-hydroxyethyl,
2-hydroxyisopropyl, acetyl, 2-hydroximino-ethyl,
2-methoximino-ethyl, acetoxymethyl, methoxycarbonyl, methoxy,
ethoxy or trifluoromethoxy; and R.sub.5 and R.sub.6 are hydrogen;
and R.sub.7 is phenyl, 4-fluorophenyl or 4-chlorophenyl; and
R.sub.8 is hydrogen or C.sub.1-C.sub.4fluoroalkano- yl.
6. A compound according to claim 1, wherein R.sub.1, R.sub.2,
R.sub.3, R.sub.5, R.sub.6 and R.sub.8 are all hydrogen and R.sub.4
is hydrogen, hydroxy, cyano, fluorine, chlorine, bromine, methyl,
tert.butyl, methylthio, trifluoromethyl, cyanomethyl, 2-cyanoethyl,
hydroxymethyl, 1-hydroxyethyl, 2-hydroxyisopropyl, acetyl,
2-hydroximino-ethyl, 2-methoximino-ethyl, acetoxymethyl, and
R.sub.7 is phenyl, 4-fluorophenyl or 4-chlorophenyl.
7. A compound according to claim 1, characterized by subformula IA
290wherein R.sub.1 is hydrogen, C.sub.1-C.sub.4alkyl, or is a group
--CO--R.sub.9 or --CO--OR.sub.10; and R.sub.2 is hydrogen or
C.sub.1-C.sub.4alkyl; or R.sub.1 and R.sub.2 together form the
group --N.dbd.CR.sub.9--NR.sub.10R.sub.11; and R.sub.4 is hydrogen,
cyano, hydroxy, C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.6aminoalkyl,
C.sub.1-C.sub.8alkanoyloxy-C.sub.1-C.sub.4alkyl,
C.sub.1-C.sub.8alkanoyla- mino-C.sub.1-C.sub.4alkyl,
C.sub.1-C.sub.4alkoxy-C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6hydroxyalkyl or C.sub.1-C.sub.4cyanoalkyl, and
R.sub.9 is hydrogen, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6haloalkyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.3-C.sub.7cycloalkyl-C.sub.1-C.sub.4alkyl- ,
C.sub.1-C.sub.4alkyl-C.sub.3-C.sub.7cycloalkyl-C.sub.1-C.sub.4alkyl,
aryl, aryl-C.sub.1-C.sub.4alkyl, heteroaryl or
heteroaryl-C.sub.1-C.sub.4- alkyl; R.sub.10 is
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl,
C.sub.3-C.sub.7cycloalkyl-C.sub.1-C.sub.4alkyl or
C.sub.1-C.sub.4alkoxy-C- .sub.1-C.sub.6alkyl; and R.sub.12 is
halogen, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4alkoxy,
C.sub.1-C.sub.4haloalkyl and C.sub.1-C.sub.4haloalkoxy, and
R.sub.13 is C.sub.1-C.sub.4alkyl.
8. A compound according to claim 1, characterized by subformula IB
291wherein R.sub.4 is hydrogen, hydroxy, cyano,
C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.6aminoalkyl,
C.sub.1-C.sub.8alkanoyloxy-C.sub.1-C.sub.4alky- l,
C.sub.1-C.sub.8alkanoylamino-C.sub.1-C.sub.4alkyl,
C.sub.1-C.sub.4alkoxy-C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6hydroxyalkyl or C.sub.1-C.sub.4cyanoalkyl, and
R.sub.12 is halogen, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4alkoxy,
C.sub.1-C.sub.4haloalkyl and C.sub.1-C.sub.4haloalkoxy.
9. A compound according to claim 1, selected from the group
comprising
N-[4-(2-amino-4-phenyl-thiazol-5-yl)-pyrimidin-2-yl]-N-phenyl-amine,
N-{4-[2-amino-4-(4-fluoro-phenyl)-thiazol-5-yl]-pyrimidin-2-yl}-N-phenyl--
amine;
N-[4-(2-amino-4-phenyl-thiazol-5-yl)-pyrimidin-2-yl]-N-[3-(1-hydrox-
yethyl)-phenyl]-amine;
N-{4-[2-amino-4-(4-fluoro-phenyl)-thiazol-5-yl]-pyr- imidin-2-yl
}-N-[3-(1-hydroxyethyl)-phenyl]-amine; N-[4-(2-amino-4-phenyl--
thiazol-5-yl)-pyrimidin-2-yl]-N-[3-(1-hydroxy-1-methylethyl)-phenyl]-amine-
;
N-{4-[2-amino-4-(4-fluoro-phenyl)-thiazol-5-yl]-pyrimidin-2-yl}-N-[3-(1--
hydroxy-1-methylethyl)-phenyl]-amine; N-[4-(2-amino-4-phenyl,
thiazol-5-yl)-pyrimidin-2-yl]-N-(3-acetyl-phenyl)-amine;
N-{4-[2-amino-4-(4-fluoro-phenyl)-thiazol-5-yl]-pyrimidin-2-yl}-N-(3-acet-
yl-phenyl)-amine;
N-[4-(2-amino-4-thiazol-5-yl)-pyrimidin-2-yl]-N-(3-cyano-
-phenyl)-amine;
N-{4-[2-amino-4-(4-fluoro-phenyl)-thiazol-5-yl]-pyrimidin--
2-yl}-(3-cyano-phenyl)-amine;
{4-[2-acetylamino-4-(4-fluoro-phenyl)-thiazo-
l-5-yl]-pyrimidin-2-yl}-N-(3-acetoxymethyl-phenyl)-amine;
N-[4-(2-amino-4-phenyl-thiazol-5-yl)-pyrimidin-2-yl]-N-(3-methoxy-phenyl)-
-amine;
N-{4-[2-amino-4-(4-fluoro-phenyl)-thiazol-5-yl]-pyrimidin-2-yl}-N--
(3-methoxy-phenyl)-amine;
N-[4-(2-amino-4-phenyl-thiazol-5-yl)-pyrimidin-2-
-yl]-N-(3-cyano-phenyl)-amine;
N-[4-(2-amino-4-phenyl-thiazol-5-yl)-pyrimi-
din-2-yl]-N-(4-fluoro-phenyl)-amine;
N-{4-[2-amino-4-(4-fluoro-phenyl)-thi-
azol-5-yl]-pyrimidin-2-yl}-N-(3-cyano-phenyl)-amine;
N-[4-(2-amino-4-phenyl-thiazol-5-yl)-pyrimidin-2-yl]-N-(3-cyanomethyl-phe-
nyl)-amine; and
N-{4-[2-amino-4-(4-fluoro-phenyl)-thiazol-5-yl]-pyrimidin--
2-yl}-N-(3-cyanomethyl-phenyl)-amine.
10. A process for the preparation of the compound according to
claim 1, comprising a) reacting a compound of formula II 292
wherein R.sub.1, R.sub.2 and R.sub.7 are as defined for formula I
and Y stands for a leaving group such as halogen, alkylthio,
alkylsulfinyl, alkylsulfonyl, with an aniline of the formula 293
wherein R.sub.3, R.sub.4, R.sub.5, R.sub.6 and R.sub.8 are as
defined for formula I, or b) reacting a compound of formula VIII
294 wherein R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7 and R.sub.8
are as defined for formula I and Z is a leaving group such as
halogen, C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.4alkylsulfinyl or
C.sub.1-C.sub.4alkylsulfonyl with an amine of the formula
HNR.sub.1R.sub.2.wherein R.sub.1 and R.sub.2 are as defined for
formula I in claim 1.
11. A composition for controlling and protecting against
phytopathogenic microorganisms, comprising a compound of formula I
according to claim 1 as active ingredient together with a suitable
carrier.
12. The use of a compound of formula I according to claim 1 in
protecting plants against infestation by phytopathogenic
microorganisms.
13. A method of controlling and preventing an infestation of crop
plants by phytopathogenic microorganisms, which comprises the
application of a compound of formula I according to claim 1 as
active ingredient to the plant, to parts of plants or to the locus
thereof.
14. A method according to claim 13, wherein the phytopathogenic
microorganisms are fungal organisms.
Description
[0001] The present invention relates to novel
N-[4-(2-amino-thiazol-5-yl)-- pyrimidin-2-yl]-N-phenyl-amine
derivatives, to a method of protecting plants against attack or
infestation by phytopathogenic organisms, such as nematodes or
insects or especially microorganisms, preferably fungi, bacteria
and viruses, or combinations of two or more of these organisms, by
applying an
N-[4-(2-amino-thiazol-5-yl)-pyrimidin-2-yl]-N-phenyl-amine
derivative as specified hereinafter to a part and/or to the site of
a plant, to the use of said derivative for protecting plants
against said organisms, and to compositions comprising said
derivative as the active component. The invention further relates
to the preparation of these novel
N-[4-(2-amino-thiazol-5-yl)-pyrimidin-2-yl]-N-phenyl-amine
derivatives.
[0002] Certain N-phenyl-N-(4-thiazolyl-pyrimidin-2-yl)-amine
derivatives have been described in the art, e.g. in the PCT patent
applications WO 97/19065, WO 01/29009 and WO 01/30778, as having
pharmacological properties, mainly as tumor-inhibiting anti-cancer
substances.
[0003] Surprisingly, it has now been found that the new
N-[4-(2-amino-thiazol-5-yl)-pyrimidin-2-yl]-N-phenyl-amine
derivatives according to the present invention are effective in
plant protection showing advantageous properties in the treatment
of plant diseases caused by phytopathogenic microorganisms. Further
the fungicidal activity allows to employ the compounds according to
present invention for controlling fungi in related areas, e.g. in
protection of technical materials, including wood and wood related
technical products, in food storage, in hygiene management,
etc..
[0004] The novel
N-[4-(2-amino-thiazol-5-yl)-pyrimidin-2-yl]-N-phenyl-amin- e
derivatives according to the invention are those of the formula I
1
[0005] wherein
[0006] R.sub.1 is hydrogen, C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.3-C.sub.7cycloalkyl-C.sub.1-C.sub.4alkyl- ,
C.sub.1-C.sub.4alkyl-C.sub.3-C.sub.7cycloalkyl-C.sub.1-C.sub.4alkyl,
C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6hydroxyalkyl,
C.sub.1-C.sub.4alkoxy-C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6aminoalkyl,
C.sub.1-C.sub.4alkyl-C.sub.1-C.sub.6aminoalkyl,
di(C.sub.1-C.sub.4alkyl)-- C.sub.1-C.sub.6aminoalkyl,
aryl-C.sub.1-C.sub.4alkyl, heteroaryl-C.sub.1-C.sub.4alkyl, or a
group --CO--R.sub.9, --CO--OR.sub.10, --CO--NR.sub.10R.sub.11, or
--NR.sub.10R.sub.11;
[0007] R.sub.2 is hydrogen, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6haloalkyl- , C.sub.1-C.sub.6hydroxyalkyl,
C.sub.1-C.sub.4alkoxy-C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6aminoalkyl,
C.sub.1-C.sub.4alkyl-C.sub.1-C.sub.6aminoalkyl or a group
--CO--R.sub.9;
[0008] R.sub.1 and R.sub.2 together with the nitrogen to which they
are bound form an optionally substituted N-linked saturated or
unsaturated N-ring system which may contain oxygen or sulfur as a
ring member, or form a group
--N.dbd.CR.sub.9--NR.sub.10R.sub.11;
[0009] R.sub.3 is hydrogen, halogen or C.sub.1-C.sub.4alkyl;
[0010] R.sub.4 is hydrogen, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6haloalkyl- , C.sub.1-C.sub.6cyanoalkyl,
C.sub.3-C.sub.7cycloalkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6haloalkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.2-C.sub.6haloalkynyl, amino, C.sub.1-C.sub.6alkylamino,
di(C.sub.1-C.sub.4alkyl)-amino, halogen, hydroxy, mercapto, cyano,
C.sub.1-C.sub.6alkoxy, C.sub.2-C.sub.6alkenylox- y,
C.sub.2-C.sub.6alkynyloxy, C.sub.1-C.sub.6haloalkoxy,
C.sub.1-C.sub.8alkanoyloxy-C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylthio- , C.sub.1-C.sub.6alkylsulfinyl,
C.sub.1-C.sub.6alkylsulfonyl, C.sub.1-C.sub.6hydroxyalkyl,
C.sub.1-C.sub.4alkoxy-C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6aminoalkyl,
C.sub.1-C.sub.4alkyl-C.sub.1-C.sub.6aminoalkyl- ,
di(C.sub.1-C.sub.4alkyl)-C.sub.1-C.sub.6aminoalkyl,
C.sub.1-C.sub.8alkoxycarbonyl,
C.sub.1-C.sub.8alkanoyl-C.sub.1-C.sub.6ami- noalkyl, optionally
substituted heterocyclyl, optionally substituted aryl, optionally
substituted heteroaryl, or a group --CO--R.sub.9, --O--CO--R.sub.9,
--NH--CO--R.sub.9, --(C.sub.1-C.sub.6alkylene-)-CO--R.s- ub.9,
--C(--O--C.sub.1-C.sub.6alkylene-O--)--R.sub.9,
--C(.dbd.NOR.sub.8)--R.sub.9 or --CO--NR.sub.10R.sub.11;
[0011] R.sub.5 is hydrogen, hydroxy, halogen, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkoxy or C.sub.1-C.sub.6haloalkyl;
[0012] R.sub.6 is hydrogen, C.sub.1-C.sub.6alkyl or
C.sub.1-C.sub.6haloalkyl;
[0013] R.sub.7 is thienyl , pyridinyl or aryl each optionally
substituted with one to three substituents independently selected
from the group comprising halogen, C.sub.1-C.sub.4alkyl,
C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4haloalkyl and
C.sub.1-C.sub.4haloalkoxy;
[0014] R.sub.8 is hydrogen, C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.1-C.sub.4alkoxy-C.sub.1-C.sub.6alkyl, or a group
--CO--R.sub.9 or --CO--OR.sub.10;
[0015] R.sub.9 is hydrogen, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6haloalkyl- , C.sub.3-C.sub.7cycloalkyl,
C.sub.3-C.sub.7cycloalkyl-C.sub.1-C.sub.4alky- l, aryl,
C.sub.1-C.sub.4alkyl-C.sub.3-C.sub.7cycloalkyl-C.sub.1-C.sub.4alk-
yl, aryl-C.sub.1-C.sub.4alkyl, heteroaryl or
heteroaryl-C.sub.1-C.sub.4alk- yl;
[0016] R.sub.10 is C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl,
C.sub.3-C.sub.7cycloalkyl-C.sub.1-C.sub.4alkyl or
C.sub.1-C.sub.4alkoxy-C- .sub.1-C.sub.6alkyl;
[0017] R.sub.11 is C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.3-C.sub.7cycloalkyl-C.sub.1-C.sub.4alkyl,
C.sub.1-C.sub.4alkoxy-C.s- ub.1-C.sub.6alkyl, aryl or heteroaryl ;
or a salt thereof.
[0018] The symbols and generic expressions used above are defined
as below. Where radicals are combined from other sub-radicals, the
definition of resulting new radical likewise follows from the
combination of the definitions of said sub-radicals.
[0019] In this document "halogen" or the prefix "halo" shall
include fluorine, chlorine, bromine and iodine. Preferably, this
definition designates substitution with fluorine or chlorine.
[0020] Alkyl--as a group per se and as a structural element of
hydroxyalkyl, aminoalkyl, dialkylamino, cycloalkylalkyl, alkoxy,
alkoxyalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkenyl,
alkynyl, alkenylyoxy, alkynyloxy, alkylene, alkanoyl, alkanoyloxy,
alkanoylamino, arylalkyl, heteroarylalkyl, haloalkyl or
haloalkoxy--is preferably C.sub.1-C.sub.6alkyl, more preferably
C.sub.1-C.sub.4alkyl. The alkyl, alkenyl and alkynyl radicals may
be straight-chain or branched. This applies also to the alkyl,
alkenyl or alkynyl parts of other alkyl-, alkenyl- or
alkynyl-containing groups. Depending upon the number of carbon
atoms mentioned, alkyl on its own or as part of another substituent
is to be understood as being, for example, methyl, ethyl, propyl,
butyl, pentyl, hexyl, heptyl, octyl and the isomers thereof, for
example isopropyl, isobutyl, tert-butyl or sec-butyl, isopentyl or
tert-pentyl. In many cases the short chain alkyl groups methyl or
ethyl are preferred.
[0021] Alkoxy includes methoxy, ethoxy, propyloxy, isopropyloxy,
butoxy, isobutyloxy, sec-butyloxy, tert-butyloxy, and the diverse
pentyloxy and hexyloxy.
[0022] Depending upon the number of carbon atoms mentioned, alkenyl
as a group or as a structural element of other groups is to be
understood as being, for example, ethenyl, allyl, 1-propen-1-yl,
2-propen-1-yl, 1-propen-3-yl, 1-buten-2-yl, 1-buten-3-yl,
1-penten-1-yl, 2-penten-1-yl, 1-penten-3-yl, hexen-1-yl,
4-methyl-3-pentenyl or 4-methyl-3-hexenyl. Optionally substituted
alkenyl groups carry one to four, preferably not more than two
further substituents selected from the group halogen,
C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4alkylthio, phenyl,
halophenyl, C.sub.1-C.sub.4alkylphenyl, benzyl, halobenzyl and
C.sub.1-C.sub.4alkylbenzyl. Examples are stryryl, chloroallyl,
dichloroallyl, trichlorovinyl, 4,4,4-trifluoro-2-butenyl.
[0023] Alkynyl as a group or as a structural element of other
groups is for example, ethynyl, propyn-1-yl, propyn-2-yl,
butyn-1-yl, butyn-2-yl, 1-methyl-2-butynyl, hexyn-1-yl,
1-ethyl-2-butynyl or octyn-1-yl. Optionally substituted alkynyl
groups carry one to four, preferably not more than two further
substituents selected from the group halogen,
C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4alkylthio, phenyl,
halophenyl, C.sub.1-C.sub.4alkylphenyl, amino,
C.sub.1-C.sub.4alkylamino, di-(C.sub.1-C.sub.4alkyl)-amino, benzyl,
halobenzyl and C.sub.1-C.sub.4alkylbenzyl. Examples are
phenylethinyl, phenylpropargyl, chloropropargyl or
5,5,5-trifluoro-2-pentinyl.
[0024] Alkenyloxy and alkynyloxy have analogous designations,
employing the exemplified alkenyl and alkynyl radicals.
[0025] Alkylene designates a bivalent bridge member, being linked
at both ends of the hydrocarbon chain, which may be straight or
branched. Typical examples are methylene, 1,2-ethylene,
1-methyl-1,2-ethylene, 1,2-dimethyl-1,2-ethylene,
1,1-dimethyl-1,2-ethylene, 1-ethyl-1,2-ethylene,
1-propyl-1,2-ethylene, 1-butyl-1,2-ethylene, 1,3-propylene, etc..
Where alkylene is attached to two oxygen atoms at both ends, and
both oxygen atoms are in turn bound to the same carbon atom as in
the definition of R.sub.4, then the functional group is that of a
ketal.
[0026] Cycloalkyl is, depending upon the number of carbon atoms
mentioned, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
bicyclopentyl, bicyclohexyl or cycloheptyl. Likewise,
cycloalkyl-alkyl or alkyl-cycloalkyl-alkyl encompass
cyclopropylmethyl, cyclopropylethyl, cyclopentylmethyl,
cyclohexylmethyl, cyclopentylethyl, cyclohexylethyl,
methyl-cyclopropylmethyl, methyl-cyclopropylethyl,
dimethyl-cyclopropylmethyl, dimethyl-cyclopropylethyl,
methyl-cyclopentylmethyl, methyl-cyclohexylmethyl,
methyl-cyclopentylethyl, methyl-cyclohexylethyl,
ethyl-cyclopentylmethyl, ethyl-cyclohexylmethyl,
ethyl-cyclopentylethyl, ethyl-cyclohexylethyl,
dimethyl-cyclopentylmethyl, dimethyl-cyclohexylmethyl,
dimethyl-cyclopentylethyl or dimethyl-cyclohexylethyl, etc..
[0027] Hydroxyalkyl preferably encompasses hydroxymethyl,
1-hydroxyethyl, 1-hydroxypropyl, 2-hydroxyethyl, 2-hydroxypropyl,
2-hydroxy-2-methyl-ethy- l, 3-hydroxypropyl and various
hydroxybutyl radicals.
[0028] Alkoxyalkyl is meant to include without limiting the
definition thereof: methoxymethyl, ethoxymethyl, propyloxymethyl,
isopropyloxymethyl, butyloxymethyl, 2-methoxyethyl, 2-ethoxyethyl,
2-propyloxyethyl, 2-isopropyloxyethyl, 2-butyloxyethyl,
1-methoxyethyl, 1-ethoxyethyl, 1-propyloxyethyl,
1-isopropyloxyethyl, 1-butyloxyethyl, 1-methoxypropyl,
1-ethoxypropyl, 1-propyloxypropyl, 1-isopropyloxypropyl,
1-butyloxypropyl, 2-methoxypropyl, 2-ethoxypropyl,
2-propyloxypropyl, 2-isopropyloxypropyl, 2-butyloxypropyl,
3-methoxypropyl, 3-ethoxypropyl, 3-propyloxypropyl,
3-isopropyloxypropyl, 3-butyloxypropyl, methoxybutyl, ethoxybutyl,
propyloxybutyl, and butyloxybutyl.
[0029] Alkoxycarbonyl is for example: methoxycarbonyl,
ethoxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl,
butyloxycarbonyl, s-butyloxycarbonyl, or terbutyloxycarbonyl.
[0030] Within this document alkanoyl includes the aliphatic acyl
radicals, e.g. formyl, acetyl, propionyl, isopropionyl, butyryl,
isobutyryl, sec-butyryl, tert-butyryl, valeryl, isovaleryl,
sec-valeryl and pivaloyl. These radicals are frequently employed in
the alkanoyloxyalkyl and alkanoylaminoalkyl groups as defined for
this invention.
[0031] Aminoalkyl includes aminomethyl, aminoethyl, aminopropyl,
aminobutyl and the isomeric forms thereof. Likewise alkylaminoalkyl
and dialkylaminoalkyl include for example methylaminomethyl,
ethylaminomethyl, propylaminomethyl, methylaminoethyl,
ethylaminoethyl, propylaminoethyl, methylaminopropyl,
ethylaminopropyl, dimethylaminomethyl, dimethylaminoethyl,
dimethylaminopropyl. ethyl-methylaminomethyl,
ethyl-methylaminoethyl, ethyl-methylaminomethyl,
ethyl-methylaminopropyl, etc..
[0032] Haloalkyl includes halogenated alkyl, preferably based on
C.sub.1-C.sub.6haloalkyl, more preferably on C.sub.1-C.sub.4alkyl,
which is linear or branched, and is substituted by one or more, for
example in case of substitution with halogen atoms all hydrogens of
the basic hydrocarbon structure may be replaced by halogen atoms,
being all identical or different. Typical examples are CHCl.sub.2,
CH.sub.2F, CCl.sub.3, CH.sub.2Cl, CHF.sub.2, CF.sub.3,
CH.sub.2CH.sub.2Br, C.sub.2Cl.sub.5, CH.sub.2Br, CHClBr,
CF.sub.3CH.sub.2, C.sub.2F.sub.5, C.sub.3F.sub.7, C.sub.4F.sub.9,
C.sub.5F.sub.11, CH.sub.2CH.sub.2Cl,
CH(CH.sub.3)--CH.sub.2--CH.sub.2Cl, CH.sub.2CH.sub.2F,
CH(CH.sub.3)--CH.sub.2--CH.sub.2F, C(CH.sub.3).sub.2--CH.sub.2--Cl,
C(CH.sub.3).sub.2--CH.sub.2--CF.sub.3,
C(CH.sub.3)--CH.sub.2--CH.sub.2--C- F.sub.3, etc..
[0033] Haloalkoxy includes halogenated alkoxy which preferably
based on C.sub.1-C.sub.6alkoxy, more preferably on
C.sub.1-C.sub.4alkoxy, which is linear or branched, and is
substituted by one or more, for example in the case of halo-ethyl
up to five halogen atoms. Especially fluorine is preferred as a
halogen substituent in alkoxy groups, including trifluoromethoxy
and 1,1,2,2-tetrafluoroethoxy as prominent members.
[0034] Cyanoalkyl includes without limiting the definition thereof:
cyanomethyl, 1-cyanoethyl, 2-cyanoethyl, 1-cyanopropyl,
2-cyanopropyl, 3-cyanopropyl, 1-cyanoisopropyl, 2-cyanoisopropyl,
the isomeric cyanobutyl, cyanopentyl and cyanohexyl. Cyanomethyl
and cyanoethyl are preferred.
[0035] Aryl typically includes aromatic hydrocarbon rings such as
phenyl, naphthyl, anthracenyl, phenanthrenyl and biphenyl, for
example 1,3-biphenyl and 1,4-biphenyl, with phenyl being preferred.
The same definition applies where aryl is part of arylalkyl.
[0036] The most prominent examples for arylalkyl are benzyl and
phenethyl.
[0037] Heteroaryl includes aromatic ring systems comprising mono-,
bi- or tricyclic systems wherein at least one oxygen, nitrogen or
sulfur atom is present as a ring member. The same definition
applies where heteroaryl is part of heteroarylalkyl. Examples are
of heteroaryl rings are furyl, thienyl, pyrrolyl, imidazolyl,
pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl,
oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl,
pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl,
indolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, indazolyl,
benzotriazolyl, benzothiazolyl, benzoxazolyl, quinolinyl,
isoquinolinyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinnolinyl
and naphthyridinyl.
[0038] The heteroaryl group may be bonded to the basic molecular
structure of formula I via a carbon or a nitrogen atom.
[0039] Heterocyclyl designates fully or partially hydrogenated
heteroaryl ring system as outlined above. Typical examples include
2-tetrahydrofuranyl, 3-tetrahydrofuranyl,
5-hydroxy-tetrathydrofuran-2-yl- , 2-isoxazolinyl, 3-isoxazolinyl,
4- isoxazolinyl, 5-isoxazolinyl, pyrrolidin-2-on-5-yl,
N-pyrrolidinyl, 2-pyrrolidinyl, 2-pyrrolin-5-yl, etc.
[0040] Where the above aryl and heteroaryl groups may be optionally
substituted, this means that they may carry one or more identical
or different substituents. Normally not more than three
substituents are present at the same time. Examples of substituents
of aryl or heteroaryl groups are: amino, C.sub.1-C.sub.4alkylamino,
di-C.sub.1-C.sub.4alkylamin- o, halogen, hydroxy, mercapto, cyano,
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy,
C.sub.1-C.sub.6alkylthio, C.sub.1-C.sub.6alkylsulf- inyl,
C.sub.1-C.sub.6alkylsulfonyl, C.sub.2-C.sub.6al-kenyloxy and
C.sub.2-C.sub.6alkynyloxy.
[0041] Typical examples for substituted aryl include
4-chlorophenyl, 4-bromophenyl, 3,4-dichlorophenyl,
4-chloro-3-fluorophenyl, 3-chloro-4-fluorophenyl, 4-methylphenyl,
4-ethylphenyl, 4-propargyloxyphenyl, 4-allyloxyphenyl,
3,4-dioxomethylenyl-phenyl, 3,4-dioxoethylenyl-phenyl,
3-methylphenyl, 4-fluorophenyl, 4-ethenylphenyl, 4-ethynylphenyl,
4-propylphenyl, 4-isopropylphenyl, 4-tert.butylphenyl,
4-ethoxyphenyl, 4-ethynyloxyphenyl, 4-methylmercaptophenyl,
4-methylsulfonylphenyl, 4-cyanophenyl, 4-methoxycarbonyl-phenyl,
3-bromophenyl, 3-chlorophenyl, 2-chlorophenyl, 2,4-dichlorophenyl,
3,4,5-trichlorophenyl, 3,4-difluorophenyl, 3,4-dibromophenyl,
3,4-dimethoxyphenyl, 3,4-dimethylphenyl, 3-chloro-4cyanophenyl,
4-chloro-3-cyanophenyl, 3-bromo-4-methylphenyl,
4-methoxy-3-methylphenyl, 3-fluoro-4methoxyphenyl,
4-chloro-3-methylphenyl, 4-chloro-3-trifluoromethyl-phenyl,
4-bromo-3-chlorophenyl, 4-trifluoromethylphenyl,
4-trifluoromethoxyphenyl- , 4-methoxyphenyl, etc. Typical examples
for substituted heteroaryl include 5-methyl-2-thienyl,
5-chloro-2-thienyl, 3-chloro-2-thienyl, 5-methyl-2-furyl,
4-methyl-oxazol-5-yl, 5-hydroxy-pyrazol-1-yl,
5-hydroxy-3-methyl-pyrazol-1-yl, 5-amino-3-methyl-pyrazol-1-yl,
5-amino-pyrazol-1-yl, 5-methyl-[1,3,4]-oxadiazol-2-yl,
5-ethyl-[1,3,4]-oxadiazol-2-yl, 2-amino-thiazol-4-yl,
2-methyl-thiazol4-yl, 6-chloro-pyridin-2-yl, 6-amino-pyridin-2-yl,
etc..
[0042] The N-ring system, being defined for the combination of
R.sub.1 and R.sub.2 includes primarily simple cyclic secondary
amines like pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl
and the alkyl-substituted derivatives, e.g. methyl-morpholinyl and
dimethyl-morpholinyl.
[0043] The group --N.dbd.CR.sub.9--NR.sub.10R.sub.11 includes the
various combinations of substituents for R.sub.9, R.sub.10 and
R.sub.11 including simple structures such as
--N.dbd.CH--N(CH.sub.3).sub.2,
--N.dbd.C(CH.sub.3)--N(CH.sub.3).sub.2 and
--N.dbd.C(C.sub.2H.sub.5)--N(C- H.sub.3).sub.2.
[0044] The group --CO--R.sub.9 represents an acyl radical which
includes a very wide variation of the basic acid. It encompasses
formic acid, the alkanoic acids as defined above and the aromatic
acids. Typical examples in addition to the alkanoyl radicals are
benzoyl, phenylacetyl, phenylpropionyl, -methyl-phenylacetyl,
nicotinoyl, isonicotinoyl, chlorobenzoyl, trifluoroacetyl,
pentafluoropropionyl, heptafluorobutyryl, chloroacetyl,
dichloroacetyl, trichloroacetyl, ,-dimethyl--chloropropiony- l,
cyclopropylcarbonyl, etc.. The same definitions apply where
--CO--R.sub.9 is part of --O--CO--R.sub.9 or --NH--CO--R.sub.9.
[0045] The group --CO--O--R.sub.10 represents for example
methoxycarbonyl, ethoxycarbonyl, etc.. The group
--CO--NR.sub.10R.sub.11 stands for example for methylaminocarbonyl,
ethylaminocarbonyl, propylaminocarbonyl, dimethyl-aminocarbonyl,
ethyl-methylaminocarbonyl, diethylaminocarbonyl, etc..
[0046] The presence of at least one asymmetric carbon atom in the
compounds of formula I means that the compounds may occur in
optically isomeric and enantiomeric forms. As a result of the
presence of a possible aliphatic C.dbd.C double bond, geometric
isomerism may also occur. Formula I is intended to include all
those possible isomeric forms and mixtures thereof
[0047] Certain compounds of formula I are capable of forming acid
addition salts, for example with inorganic acids, such as
hydrochloric acid, sulfuric acid or a phosphoric acid, or with
suitable organic carboxylic or sulfonic acids, for example
aliphatic mono- or di-carboxylic acids, such as trifluoroacetic
acid, acetic acid, propionic acid, glycolic acid, succinic acid,
maleic acid, fumaric acid, hydroxymaleic acid, maleic acid,
tartaric acid, citric acid, oxalic acid or amino acids, such as
argentine or lysine, aromatic carboxylic acids, such as benzoic
acid, 2-phenoxy-benzoic acid, 2-acetoxy-benzoic acid, salicylic
acid, 4-aminosalicylic acid, aromatic-aliphatic carboxylic acids,
such as mandelic acid or cinnamic acid, heteroaromatic carboxylic
acids, such as nicotinic acid or isonicotinic acid, aliphatic
sulfonic acids, such as methane-, ethane- or
2-hydroxy-ethane-sulfonic acid, or aromatic sulfonic acids, for
example benzene-, p-toluene- or naphthalene-2-sulfonic acid.
[0048] Formula I according to the invention shall include all the
possible isomeric forms, as well as mixtures, e.g. racemic
mixtures, and any mixtures of rotamers.
[0049] In view of the close relationship between the compounds of
formula I in free form and in the form of their salts, including
also salts that can be used as intermediates, for example in the
purification of the compounds of formula I or in order to identify
those compounds, herein-before and hereinafter any reference to the
(free) compounds is to be understood as including also the
corresponding salts, where appropriate and expedient.
[0050] Among the compounds of formula I according to the present
invention the following groups of compounds are preferred. These
groups are those wherein
[0051] R.sub.1 is hydrogen, C.sub.1-C.sub.4alkyl or is a group
--CO--R.sub.9; or
[0052] R.sub.1 is hydrogen, methyl, trifluoroacetyl,
pentafluoropropionyl or heptafluorobutyryl; or
[0053] R.sub.1 is hydrogen or methyl; or
[0054] R.sub.1 is hydrogen, or
[0055] R.sub.2 is hydrogen or C.sub.1-C.sub.4alkyl; or
[0056] R.sub.2 is hydrogen or methyl; or
[0057] R.sub.1 and R.sub.2 are both hydrogen, or
[0058] R.sub.1 and R.sub.2 together form the group
--N.dbd.CR.sub.9--NR.su- b.10R.sub.11; or
[0059] R.sub.1 and R.sub.2 together form the groups
--N.dbd.CH--N(CH.sub.3).sub.2,
--N.dbd.C(CH.sub.3)--N(CH.sub.3).sub.2 or
--N.dbd.C(C.sub.2H.sub.5)--N(CH.sub.3).sub.2; or
[0060] R.sub.1 and R.sub.2 together form the groups
--N.dbd.CH--N(CH.sub.3).sub.2 or
--N.dbd.C(CH.sub.3)--N(CH.sub.3).sub.2; or
[0061] R.sub.3 is hydrogen ; or
[0062] R.sub.4 is hydrogen, hydroxy, amino, C.sub.1-C.sub.4alkyl,
C.sub.1-C.sub.4haloalkyl, C.sub.1-C.sub.4cyanoalkyl,
C.sub.1-C.sub.6alkylamino, di(C.sub.1-C.sub.4alkyl)-amino,
C.sub.1-C.sub.6aminoalkyl, halogen, mercapto, cyano,
C.sub.1-C.sub.6alkoxy, C.sub.2-C.sub.6alkenyloxy,
C.sub.2-C.sub.6alkynylo- xy, C.sub.1-C.sub.6alkylthio,
C.sub.1-C.sub.6alkylsulfinyl, C.sub.1-C.sub.6alkylsulfonyl,
C.sub.1-C.sub.6hydroxyalkyl,
C.sub.1-C.sub.4alkoxy-C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.4alkyl-C.sub.1-- C.sub.6aminoalkyl,
C.sub.1-C.sub.4alkoxycarbonyl, di(C.sub.1-C.sub.4alkyl)-
-C.sub.1-C.sub.6aminoalkyl, --CO--R.sub.9, or --NH--CO--R.sub.9;
or
[0063] R.sub.4 is hydrogen, hydroxy, cyano, C.sub.1-C.sub.4alkyl,
C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4haloalkoxy,
C.sub.1-C.sub.4haloalky- l, C.sub.1-C.sub.4cyanoalkyl,
C.sub.1-C.sub.4alkanoyloxy, C.sub.1-C.sub.4hydroxyalkyl,
C.sub.1-C.sub.4haloalkanoyloxy,
C.sub.1-C.sub.4alkanoyl-C.sub.1-C.sub.6aminoalkyl,
C.sub.1-C.sub.4alkanoyloxy-C.sub.1-C.sub.4alkyl,
C.sub.1-C.sub.4alkanoyl, C.sub.1-C.sub.4alkylthio or
C.sub.1-C.sub.4alkoxycarbonyl; or
[0064] R.sub.4 is hydrogen, hydroxy, cyano, fluorine, chlorine,
bromine, methyl, tert. butyl, methylthio, trifluoromethyl,
cyanomethyl, 2-cyanoethyl, hydroxymethyl, 1-hydroxyethyl,
2-hydroxyisopropyl, acetyl, 2-hydroximino-ethyl,
2-methoximino-ethyl, acetoxymethyl, methoxycarbonyl, methoxy,
ethoxy or trifluoromethoxy; or
[0065] R.sub.5 is hydrogen, hydroxy, methoxy or methylthio; or
[0066] R.sub.5 is hydrogen or hydroxy; or
[0067] R.sub.5 is hydrogen; or
[0068] R.sub.6 is hydrogen, or methoxy; or
[0069] R.sub.6is hydrogen; or
[0070] R.sub.7 is 4-pyridyl or optionally substituted aryl carrying
one to three substituents independently selected from the group
comprising halogen, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4alkoxy,
C.sub.1-C.sub.4haloalkyl and C.sub.1-C.sub.4haloalkoxy; or
[0071] R.sub.7 is phenyl or halophenyl; or
[0072] R.sub.7 is phenyl, 4-fluorophenyl or 4-chlorophenyl; or
[0073] R.sub.8 is hydrogen, C.sub.1-C.sub.4alkanoyl,
C.sub.1-C.sub.4haloalkanoyl or C.sub.1-C.sub.4alkyl; or
[0074] R.sub.8 is hydrogen or C.sub.1-C.sub.4fluoroalkanoyl; or
[0075] R.sub.8 is hydrogen.
[0076] Further preferred subgroups of formula I are those compounds
wherein:
[0077] a) R.sub.3, R.sub.6 and R.sub.8 are all hydrogen, or
[0078] b) R.sub.1 is hydrogen, C.sub.1-C.sub.4alkyl, or is a group
--CO--R.sub.9; and R.sub.2 is hydrogen or C.sub.1-C.sub.4alkyl; or
R.sub.1 and R.sub.2 together form the group
--N.dbd.CR.sub.9--NR.sub.10R.- sub.11; R.sub.3 is hydrogen or
methyl; and R.sub.4 is hydrogen, hydroxy, amino,
C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4haloalkyl,
C.sub.1-C.sub.4cyanoalkyl, C.sub.1-C.sub.6alkylamino,
di(C.sub.1-C.sub.4alkyl)-amino, C.sub.1-C.sub.6aminoalkyl, halogen,
mercapto, cyano, C.sub.1-C.sub.6alkoxy, C.sub.2-C.sub.6alkenyloxy,
C.sub.2-C.sub.6alkynyloxy, C.sub.1-C.sub.6alkylthio,
C.sub.1-C.sub.6alkylsulfinyl, C.sub.1-C.sub.6alkylsulfonyl,
C.sub.1-C.sub.6hydroxyalkyl,
C.sub.1-C.sub.4alkoxy-C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.4alkyl-C.sub.1-C.sub.6aminoalkyl,
di(C.sub.1-C.sub.4alkyl)-- C.sub.1-C.sub.6aminoalkyl,
C.sub.1-C.sub.4alkoxycarbonyl; --CO--R.sub.9, or --NH--CO--R.sub.9;
and R.sub.5 is hydrogen, hydroxy, methoxy or methylthio; and
R.sub.6 is hydrogen or methoxy; and R.sub.7 is 4-pyridyl or
optionally substituted aryl carrying one to three substituents
independently selected from the group comprising halogen,
C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4alkoxy,
C.sub.1-C.sub.4haloalkyl and C.sub.1-C.sub.4haloalkoxy; and R.sub.8
is hydrogen, C.sub.1-C.sub.4alkanoyl, C.sub.1-C.sub.4haloalkanoyl
or C.sub.1-C.sub.4alkyl; or
[0079] c) R.sub.1 is hydrogen, methyl, trifluoroacetyl,
pentafluoropropionyl or heptafluorobutyryl; and R.sub.2 is hydrogen
or C.sub.1-C.sub.4alkyl; or R.sub.1 and R.sub.2 are both hydrogen,
or R.sub.1 and R.sub.2 together form the groups
--N.dbd.CH--N(CH.sub.3).sub.- 2 or
--N.dbd.C(CH.sub.3)--N(CH.sub.3).sub.2; and R.sub.3 is hydrogen or
methyl; and R.sub.4 is hydrogen, hydroxy, C.sub.1-C.sub.4alkyl,
C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4haloalkoxy,
C.sub.1-C.sub.4haloalky- l, C.sub.1-C.sub.4cyanoalkyl,
C.sub.1-C.sub.4alkanoyloxy, C.sub.1-C.sub.4hydroxyalkyl,
C.sub.1-C.sub.4haloalkanoyloxy,
C.sub.1-C.sub.4alkanoyl-C.sub.1-C.sub.6aminoalkyl,
C.sub.1-C.sub.4alkanoyloxy-C.sub.1-C.sub.4alkyl,
C.sub.1-C.sub.4alkanoyl, C.sub.1-C.sub.4alkylthio or
C.sub.1-C.sub.4alkoxycarbonyl; and R.sub.5 is hydrogen or hydroxy;
and R.sub.6 is hydrogen; and R.sub.7 is phenyl or halophenyl; and
R.sub.8 is hydrogen or C.sub.1-C.sub.4fluoroalkanoyl; or
[0080] d) R.sub.1 is acetyl; and R.sub.2 is hydrogen or methyl; or
R.sub.1 and R.sub.2 together form the groups
--N.dbd.CH--N(CH.sub.3).sub.2 or
--N.dbd.C(CH.sub.3)--N(CH.sub.3).sub.2; and R.sub.3 is hydrogen;
and R.sub.4 is hydrogen, hydroxy, cyano, fluorine, chlorine,
bromine, methyl, tert. butyl, methylthio, trifluoromethyl,
hydroxymethyl, cyanomthyl, 2-cyanoethyl, 1-hydroxyethyl,
2-hydroxyisopropyl, acetyl, 2-hydroximino-ethyl,
2-methoximino-ethyl, acetoxymethyl, methoxycarbonyl, methoxy,
ethoxy or trifluoromethoxy; and R.sub.5 and R.sub.6 are hydrogen;
and R.sub.7 is phenyl, 4-fluorophenyl or 4-chlorophenyl; and
R.sub.8 is hydrogen or C.sub.1-C.sub.4fluoroalkanoyl; or
[0081] e) R.sub.1, R.sub.2, R.sub.3, R.sub.5, R.sub.6 and R.sub.8
are all hydrogen and R.sub.4 is hydrogen, hydroxy, cyano, fluorine,
chlorine, bromine, methyl, tert. butyl, methylthio,
trifluoromethyl, cyanomethyl, 2-cyanoethyl, hydroxymethyl,
1-hydroxyethyl, 2-hydroxyisopropyl, acetyl, 2-hydroximino-ethyl,
2-methoximino-ethyl, acetoxymethyl, and R.sub.7 is phenyl,
4-fluorophenyl or 4-chlorophenyl.
[0082] Other preferred subgroups are characterized by subformula IA
2
[0083] wherein R.sub.1 is hydrogen, C.sub.1-C.sub.4alkyl, or is a
group --CO--R.sub.9 or --CO--OR.sub.10; and R.sub.2 is hydrogen or
C.sub.1-C.sub.4alkyl; or R.sub.1 and R.sub.2 together form the
group --N.dbd.CR.sub.9--NR.sub.10R.sub.11; and R.sub.4 is hydrogen,
cyano, hydroxy, C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.6aminoalkyl,
C.sub.1-C.sub.8alkanoyloxy-C.sub.1-C.sub.4alkyl,
C.sub.1-C.sub.8alkanoyla- mino-C.sub.1-C.sub.4alkyl,
C.sub.1-C.sub.4alkoxy-C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6hydroxyalkyl or C.sub.1-C.sub.4cyanoalkyl, and
R.sub.9 is hydrogen, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6haloalkyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.3-C.sub.7cycloalkyl-C.sub.1-C.sub.4alkyl- ,
C.sub.1-C.sub.4alkyl-C.sub.3-C.sub.7cycloalkyl-C.sub.1-C.sub.4alkyl,
aryl, aryl-C.sub.1-C.sub.4alkyl, heteroaryl or
heteroaryl-C.sub.1-C.sub.4- alkyl; R.sub.10 is
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl,
C.sub.3-C.sub.7cycloalkyl-C.sub.1-C.sub.4alkyl or
C.sub.1-C.sub.4alkoxy-C- .sub.1-C.sub.6alkyl; and R.sub.12 is
halogen, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4alkoxy,
C.sub.1-C.sub.4haloalkyl and C.sub.1-C.sub.4haloalkoxy, and
R.sub.13 is C.sub.1-C.sub.4alkyl; or by subformula IB 3
[0084] wherein R.sub.4 is hydrogen, hydroxy, cyano,
C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.6aminoalkyl,
C.sub.1-C.sub.8alkanoyloxy-C.sub.1-C.sub.4alky- l,
C.sub.1-C.sub.8alkanoylamino-C.sub.1-C.sub.4alkyl,
C.sub.1-C.sub.4alkoxy-C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6hydroxyalkyl or C.sub.1-C.sub.4cyanoalkyl, and
R.sub.12 is halogen, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4alkoxy,
C.sub.1-C.sub.4haloalkyl and C.sub.1-C.sub.4haloalkoxy.
[0085] Preferred individual compounds of the formula I 4
[0086]
N-[4-(2-amino-4-phenyl-thiazol-5-yl)-pyrimidin-2-yl]-N-phenyl-amine-
,
[0087]
N-{4-[2-amino-4-(4-fluoro-phenyl)-thiazol-5-yl]-pyrimidin-2-yl}-N-p-
henyl-amine;
[0088]
N-[4-(2-amino-4-phenyl-thiazol-5-yl)-pyrimidin-2-yl]-N-[3-(1-hydrox-
yethyl)-phenyl]-amine;
[0089]
N-{4-[2-amino-4-(4-fluoro-phenyl)-thiazol-5-yl]-pyrimidin-2-yl}-N-[-
3-(1-hydroxyethyl)-phenyl]-amine;
[0090]
N-[4-(2-amino-4-phenyl-thiazol-5-yl)-pyrimidin-2-yl]-N-[3-(1-hydrox-
y-1-methylethyl)-phenyl]-amine;
[0091]
N-{4-[2-amino-4-(4-fluoro-phenyl)-thiazol-5-yl]-pyrimidin-2-yl}-N-[-
3-(1-hydroxy-1-methylethyl)-phenyl]-amine;
[0092] N-[4-(2-amino-4-phenyl,
thiazol-5-yl)-pyrimidin-2-yl]-N-(3-acetyl-p- henyl)-amine;
[0093]
N-{4-[2-amino-4-(4-fluoro-phenyl)-thiazol-5-yl]-pyrimidin-2-yl}-N-(-
3-acetyl-phenyl)-amine;
[0094]
N-[4-(2-amino-4-thiazol-5-yl)-pyrimidin-2-yl]-N-(3-cyano-phenyl)-am-
ine;
[0095]
N-{4-[2-amino-4-(4-fluoro-phenyl)-thiazol-5-yl]-pyrimidin-2-yl}-(3--
cyano-phenyl)-amine;
[0096]
{4-[2-acetylamino-4-(4-fluoro-phenyl)-thiazol-5-yl]-pyrimidin-2-yl}-
-N-(3-acetoxymethyl-phenyl)-amine;
[0097]
N-[4-(2-amino-4-phenyl-thiazol-5-yl)-pyrimidin-2-yl]-N-(3-methoxy-p-
henyl)-amine;
[0098]
N-{4-[2-amino-4-(4-fluoro-phenyl)-thiazol-5-yl]-pyrimidin-2-yl}-N-(-
3-methoxy-phenyl)-amine;
[0099]
N-[4-(2-amino-4-phenyl-thiazol-5-yl)-pyrimidin-2-yl]-N-(3-cyano-phe-
nyl)-amine;
[0100]
N-[4-(2-amino-4-phenyl-thiazol-5-yl)-pyrimidin-2-yl]-N-(4-fluoro-ph-
enyl)-amine;
[0101]
N-{4-[2-amino-4-(4-fluoro-phenyl)-thiazol-5-yl]-pyrimidin-2-yl}-N-(-
3-cyano-phenyl)-amine;
[0102]
N-[4-(2-amino-4-phenyl-thiazol-5-yl)-pyrimidin-2-yl]-N-(3-cyanometh-
yl-phenyl)-amine; and
[0103]
N-{4-[2-amino-4-(4-fluoro-phenyl)-thiazol-5-yl]-pyrimidin-2-yl}-N-(-
3-cyanomethyl-phenyl)-amine.
[0104] The compounds according to the invention may be prepared
according to methods per se known in the art (this means that in
spite of employing generally known types of organic reaction steps
, that where novel compounds are produced, the respective process
of manufacture and the sequence of steps is novel because it has
not been known for be employable for the novel compound). The
procedures for the preparation of compounds of formula I may be
outlined as follows: 5
[0105] As shown in Scheme 1 the compounds of formula I may be
obtained by reaction of compounds of formula II wherein R.sub.1 and
R.sub.2 are as defined for formula I, Y stands for a leaving group
such as halogen, alkylthio, alkylsulfinyl, alkylsulfonyl and Z is a
leaving group such as halogen, C.sub.1-C.sub.4alkylthio,
C.sub.1-C.sub.4alkylsulfinyl or C.sub.1-C.sub.4alkylsulfonyl, with
an aniline of the displayed formula wherein R.sub.3, R.sub.4,
R.sub.5, R.sub.6 and R.sub.8 are as defined for formula I. In this
reaction the leaving group Y is substituted with the aniline of the
shown formula.
[0106] The anilines with substituents R.sub.3, R.sub.4, R.sub.5,
R.sub.6 and R.sub.8 are mostly commercially available or otherwise
can easily be obtained from commercial products by per se known
processes. The thiazolyl pyrimidines of formula II have especially
been developed for the synthesis of the compounds of formula I and
thus comprise another feature of the present invention.
[0107] The nucleophilic substitution of a group Y is typically
conducted in the presence of a Lewis acid using an excess of
aniline. Y stands for a leaving group, such as halogen, alkylthio,
alkylsulfinyl or alkylsulfonyl. The reaction may be carried out in
an inert solvent, such as ethers like tetrahydrofuran, dioxane,
diglyme and the like. Appropriate reaction conditions are described
for analogous reactions e.g. in U.S. Pat. Nos. 5,670,527 or
5,658,903.
[0108] Typical Lewis acids include boron trifluoride, zinc
halogenides and sulfonic acids like benzenesulfonic,
toluenesulfonic, methanesulfonic and ethanesulfonic acids. The
reaction temperature may vary within wide ranges, e.g. from
+20.degree. C. to +220.degree. C., but mostly is performed at the
boiling point of the reaction mixture.
[0109] The leaving groups are the standard ones commonly used in
organic synthesis. The relative reactivity of the leaving group X
can for examples be modulated by oxidation of the alkylthio group
to the corresponding more reactive sulfoxide or sulfone using
standard conditions.
[0110] The compounds of formula II are novel and may be prepared by
reacting a compound of the formula III with a thiourea IV. This
reaction is in the literature referred to as Hantzsch thiazole
synthesis and may be performed under reaction conditions described
in the literature for this type of ring formation. The thioureas of
formula IV are commercial products, or may be synthesized according
to known processes.
[0111] The intermediate .alpha.-halogen-.beta.-pyrimidinylacetyl
derivatives of formula m are likewise novel and have been developed
for the synthesis of the final active ingredients of this
invention. The intermediates of formula III may be prepared by
reacting an analogous .beta.-pyrimidinylacetyl derivative of
formula V with a halogenating agent. R.sub.7 is as defined for
formula I and Hal stands for a halogen atom, preferably bromine or
chlorine. Typical halogenating agents include bromine and chlorine
and its addition compounds with amines as well as copper bromide
and the like. The reaction is preferably conducted in an organic
solvent, such as acetic acid, alcohols or halogenated hydrocarbons,
such as chloroform or methylene chloride. The reaction temperature
may vary from -20.degree. C. to boiling temperature of the reaction
mixture, depending on the reactivity of the halogenated compound of
formula V. It is typically close to room temperature.
[0112] Compounds of the general formula V wherein R.sub.7 is as
defined for formula I may be prepared by reacting a
methylpyrimidine of the formula VI with a carbonic acid derivative
of formula VII. The radical X in formula VII stands for a leaving
group such as alkoxide, dialkylamine, dialkyl hydroxylamine,
halogen and acyloxy. Many of the .alpha.-pyrimidinylacetyl
derivatives of formula V are known, and the still novel ones can be
obtained according to known methods. The starting materials VI and
VII are known compounds.
[0113] The first reaction step of Scheme 1 is a type of Claisen
type ester condensation. The condensation is achieved in the
presence of strong bases, including alkoxides, such as potassium
t-butoxide or sodium t-butoxide, lithiumamides, such as LDA or
LiHMDS and metal hydrides, such as potassium or sodium hydride, and
is preferably conducted in an inert solvent. Typical solvents are
ethers, such as diethylether, glyme and THF. In certain cases the
use of more polar solvents, such as DMF, DMSO and HMPT is
preferred. The reaction is typically performed at temperatures
ranging from -78.degree. C. to the boiling point of the
solvent.
[0114] For reasons of laboratory convenience and rationalization of
work, a reasonable approach is to start the synthesis of compounds
of formula I with thiourea (intermediate IV wherein R.sub.1 and
R.sub.2 are hydrogen) and to modify the amino group NR.sub.1R.sub.2
on the stage of the intermediate of formula II by conducting a
Sandmeyer replacement reaction according to Subscheme 1a followed
by displacement of halogen by an amine HNR.sub.1R.sub.2. 6
[0115] In Subscheme 1a the radicals are defined as in Scheme 1.
[0116] Alternatively, the compounds of formula I may be obtained
according to Schemes 2 and 3. 7
[0117] According to Scheme 2 the compounds of formula I may be
obtained by reaction of compounds of formula VIII wherein R.sub.3,
R.sub.4, R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are as defined for
formula I and Z is a leaving group such as halogen,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.4alkylsulfinyl or
C.sub.1-C.sub.4alkylsulfonyl with an amine HNR.sub.1R.sub.2. The
intermediates of formula VIII represent another feature of the
present invention.
[0118] This amination reaction with a secondary amine
HNR.sub.1R.sub.2 is a typical nucleophilic substitution reaction
and may be carried out under the conditions known as common for
such reactions. The reaction may be carried out in an inert
solvent, such as ethers, dimethylformamide, dimethylsulfoxide,
alcohols, acetonitrile, and the like.
[0119] For the case that nucleophilic amines are used, this
reaction will work without the presence of an additional base;
however, when more acidic amines are employed a base may be
required. Typical bases include alkaline carbonates, such as
potassium carbonate and sodium carbonate or metal alcoholates, such
as potassium tert-butoxide. The reaction temperature may vary
within wide ranges, e.g. from room temperature to +150.degree. C.
In the case of Z being alkylthio the reactivity of the intermediate
starting material VII may be enhanced by oxidizing the leaving
group W to the corresponding sulfoxide or sulfone using standard
conditions for such transformations.
[0120] The intermediates of formula VIII may in turn be obtained by
reacting a compound of formula IX wherein R.sub.7 is defined as for
formula I, W stands for a secondary amino group, wherein the two
radicals are either C.sub.1-C.sub.4alkyl or together form an
alkylene chain, with dimethylamino being the preferred embodiment,
and Z is as defined for formula VIII, and with a guanidine of
formula X wherein the substituents R.sub.3, R.sub.4, R.sub.5,
R.sub.6 and R.sub.8 are as defined for formula I.
[0121] The guanidines of formula X are known in the art, and are
even commercially available. In contrast, the intermediates of
formula IX are novel and yet stand for another feature of the
present invention, and so is the preceding intermediate of formula
XI which had to be especially created in order to enable this
synthesis pathway of the active ingredients of formula I.
[0122] This cyclization reaction step (IX+X?VIII) may be carried
out in the presence or absence of a solvent. The presence of a
solvent is preferred in laboratory scale, while technical scale
production prefers the variants without use of solvents. Typical
solvents for this step would include alcohols, such as ethanol,
iso-propanol, iso-butanol and the like, dimethylformamide, ethers,
such as dioxane and hydrocarbons, such as toluene. In case where
the guanidine VIII is used in form of an addition salt other then a
hydrogen carbonate the addition of an additional base as co-reagent
is required. The reaction temperature may vary within narrow
ranges, but is principally defined by the boiling temperature of
the reaction mixture. Typically, such temperatures are between
+80.degree. C. and +150.degree. C.
[0123] The compounds of the general formula IX as defined above may
be obtained by reacting an acetyl thiazole compound of formula XI
with a dialkyl-formamide acetal, such as dimethylformamide dimethyl
acetal or dimethylacetamide acetal. Alkyl in Scheme 2 represents
C.sub.1-C.sub.4alkyl, e.g. methyl while alkylene is a straight or
branched C.sub.1-C.sub.5hydrocarbon bridge like methylene,
ethylene, methylethylene, ethylethylene or dimethylethylene. Where
desired a solvent may be used. Typical solvents include
dimethylformamide and dioxane. The reaction temperature lies
typically between +80.degree. C. and +120.degree. C.
[0124] Compounds of the general formula XI may be obtained by
metallating a thiazole of the formula XII with a metallating agent
such as alkyllithium and reacting it with an acetylating agent AcT
wherein T is a leaving group being typically the
N,O-dimethylhydroxylamino radical (Weinrebs amide), or otherwise
preferably N,N-dimethylamino. Metallation is performed in a inert
solvent, such as ethers like diethyl ether, tetrahydrofuran or
alkanes and mixtures thereof. The metallating agent is typically
butyllithium. The reaction temperature lies in the range of
-78.degree. C. to 0C. The metallated transitional intermediate
formed from the thiazole is in this reaction quenched with an acyl
equivalent AcT. The thiazole compounds of formula XII is described
in literature.
[0125] Alternatively compounds of formula XI, where Z stands for
C.sub.1-C.sub.4alkylthio or optionally substituted amino can be
prepared by reacting a compound of formula XIV with halogenated
acetone, e.g. bromoacetone. The compounds of formula XIV are known
in the art. 8
[0126] The Negishi type coupling reaction allows to build up the
basic structure of the active ingredients of formula I in a
different manner. This may have advantages for some specific
substitution patterns in formula I.
[0127] In Scheme 3 the radicals are as defined above. The reaction
conditions may in general correspond to the following:
[0128] Deprotection of compounds of the general formula VIII to
form compounds of the formula I may be accomplished by treating a
compound of the general formula VIII with an acid using standard
conditions.
[0129] Compounds of the general formula VIII may be obtained in
accordance to Scheme 1 by displacement of iodine by an aniline
under reaction conditions already described above.
[0130] Compounds of the general formula XVI may be obtained by
reacting an aminothiazole XV according to the method of Negishi.
Thus a compound of formula XV is allowed to react with a
metallating agent, such as n-hexyllithium or n-butyllithium, in an
inert solvent, such as ethers like tetrahydrofuran, glyme, diethyl
ether and the like, to give a dilithiated intermediate. The
reaction temperature may vary within ranges. It typically lies
between -78.degree. C. to 0C. The lithiated species is in-situ
transmetallated using at least stoichiometric amounts of a zinc
salt, such as zinc chloride or zinc bromide. The thus obtained zinc
compound may then be reacted with 2,4-diiodopyrimidine in the
presence of a palladium catalyst. Typical palladium catalysts
include Pd(PPh.sub.3).sub.4 or Pd.sub.2dba.sub.3. The reaction
temperature of the coupling lies in the range of 0.degree. C. to
the boiling point of the reaction mixture.
[0131] For various reasons it may also be desirable to transform
one derivative of formula I into another one which is also within
the general definition of formula I.
[0132] Thus, it is for example possible to acylate compounds of the
subformula Ia wherein R.sub.1 is hydrogen using acylating agents.
9
[0133] Typical acylation agents for this purpose include carboxylic
acid chlorides, carboxylic acid anhydrides, chloroalkyl formiates,
carbamoylchlorides and the like. The acylation may be carried out
in the presence or absence of a base. The reaction temperature will
suitably lie in the range from 0.degree. C. to the boiling point of
the reaction mixture. Inert solvents may be used where desired or
indicated by the nature of the reagents. Examples of suitable bases
include alkaline metal carbonates or bicarbonates, such as
potassium carbonate or sodium hydrogen carbonate (referred to as
Schotten-Baumann conditions) or tertiary amines, such as
triethylamine or diisopropylethylamine. Examples of suitable
solvents include aromatic hydrocarbons such as toluene; ethers such
as diethyl ether, tetrahydrofuran and glyme or mixtures with
water.
[0134] If in the compound of formula Ia R.sub.2 is hydrogen, and
depending on the nucleophilicity of the acylating agent and the
reaction conditions not only mono- but also diacylated products can
be obtained. Therein R.sub.1 and R.sub.2 independently of each
other stand for identical or different --CO--R.sub.9 moieties.
Where the diacylated product appears as a by-product to the
monoacylated compound of formula Ia, the product mixtures can be
separated by crystallization or chromatography.
[0135] Derivatives of the subformula Ib 10
[0136] may be modified if desired
[0137] a) by reacting them with an amide acetal. Typical amide
acetals include dimethylformamide acetal and dimethylacetamide
acetal. The reaction is typically carried out with the pure
reagents, i.e. without the presence of a solvent. Where desired,
also inert solvents such as dimethylformamide or ethers, such as
tetrahydrofuran, glyme or dioxane, or esters may be used. The
reaction temperature lies in the range from about +50.degree. C. to
the boiling point of the mixture. or
[0138] b) by alkylating them in a reaction where the compound of
formula Ib is treated with an aldehyde in the presence of a
reducing agent (in the literature referred to as reductive
alkylation). This reaction is with advantage performed in a
solvent. Typical solvents include ethers, such as tetrahydrofuran,
glyme, acetic acid or alcohols. Reducing agents include
borohydrides, such as sodium borohydride and sodium
cyanoborohydride. The reaction temperature lies in the range from
0.degree. C. to the boiling point of the solvent.
[0139] Further derivatives of the formula I may be easily obtained
from reacting the compounds of subformula Ic 11
[0140] at the functional carbonylic group in R.sub.4, e.g. with
Grignard-reagents and other metallated radicals to yield the
corresponding tertiary alcohols. The reaction of this type is
routinely performed in inert solvents and with using an excess of
metallated agent. Typical solvents are ethers such as diethyl
ether, tetrahydrofuran, glyme and the like. The reaction
temperature lies in the range of 0.degree. C. to the boiling point
of the solvent, but is normally kept under strict control by
cooling and slow addition of the reactant of formula Ic. The
standard work-up processes allow to isolate the compounds of
formula I, wherein R.sub.4 is hydroxyalkyl in high yields and as
pure compounds.
[0141] When employing the functional intermediate of formula Id
12
[0142] additional transition metal catalyzed reactions, such as
Sonogashira, Heck, Stille and Suzuki couplings, as well as
Hartwig-Buchwald aminations offer further opportunities for
derivatization of already prepared compounds of formula I. The
indicated methods are known in the art and may be suitably adapted
to the requirements of the envisaged derivatization.
[0143] In addition to the novel active fungicidal compounds the
present invention also relates to novel starting materials and/or
intermediates and to processes for the preparation thereof. The
starting materials used and the reaction conditions chosen are
preferably such that the compounds shown in this disclosure as
being especially preferred or to be used preferably are obtained.
Especially preferred among the process conditions are those
described in the examples below, or analogous procedures.
[0144] The invention also relates to compositions which comprise
the compounds of the formula I, or a salt thereof, as an active
component, in particular plant-protecting compositions, and also to
their use in the agricultural sector or related areas.
[0145] Active compounds of the formula I are customarily used in
the form of compositions and may be added, simultaneously or
successively, to the surface or plant to be treated together with
additional active compounds. These additional active compounds may
be either fertilizers, trace element-supplying agents or other
preparations which influence plant growth. It is also possible, in
this context, to use selective herbicides, such as insecticides,
fungicides, bactericides, nematicides or molluscicides, or mixtures
of several of these preparations, additionally, where appropriate,
together with excipients, surfactants or other
administration-promoting additives which are customary in
formulation technology (designated collectively as carrier
materials herein).
[0146] Suitable excipients and additives may be solid or liquid and
are those substances which are appropriate in formulation
technology, for example natural or regenerated minerals, solvents,
dispersants, wetting agents, adhesives, thickening agents, binding
agents or fertilizers.
[0147] A preferred method for applying a compound of formula I, or
an agrochemical composition which comprises at least one of these
compounds, is administration to the leaves (foliar application).
The frequency and rate of administration depend upon the risk of
infestation by the corresponding pathogen. The compounds of formula
I can, however, also penetrate the plant through the roots via the
soil (systemic action). If the locus of the plant is impregnated
with a liquid formulation or if the substances are introduced in
solid form into the soil, e.g. in the form of granules (soil
application). In paddy rice crops, such granules can be applied in
metered amounts to the flooded rice fields. In order to treat seeds
, the compounds of formula I can, however, also be applied to the
seeds (coating), either by impregnating the grains or tubers with a
liquid formulation of the active ingredient, or by coating them
with a solid formulation.
[0148] Advantageous rates of application are in normally from 5 g
to 2 kg of active ingredient (a.i.) per hectare (ha), preferably
from 10 g to 1 kg of a.i./ha, especially from 20 g to 600 g
a.i./ha. When the compound are used as seed dressings, dosages of
from 10 mg to 1 g of active ingredient per kg seed are advantageous
employed. The agrochemical compositions generally comprise 0.1 to
99% by weight, preferably 0.1 to 95% by weight, of a compound of
formula I, 99.9 to 1% by weight, preferably 99.8 to 5% by weight,
of a solid or liquid adjuvant and 0 to 25% by weight, preferably
0.1 to 25% by weight, of a surfactant. Whereas commercial products
will preferably be formulated as concentrates, the end user will
normally employ dilute formulations.
[0149] The compositions may also comprise further auxiliaries, such
as fertilizers and other active ingredients for obtaining special
desirable biological effects.
[0150] The compounds of formula I may be used preventatively and/or
curatively in the sector of agronomics and related technical areas
as active ingredients for controlling plant pests. The active
ingredients of formula I according to the invention are notable for
their good activity even at low concentrations, for their good
plant tolerance and for their environmentally friendly nature. They
have very advantageous, especially systemic, properties and may be
used to protect a plurality of cultivated plants. Using the active
ingredients of formula I on plants or plant parts (fruit, flowers,
leaves, stems, tubers, roots) of various crops, the pests appearing
can be controlled or destroyed, whereby the parts of plants which
grow later also remain protected, e.g. from phytopathogenic
microorganisms.
[0151] The compounds I may additionally be used as a dressing to
treat seeds (fruits, tubers, corns) and plant cuttings to protect
against fungal infections and against phytopathogenic fungi
occurring in the soil.
[0152] The compounds I are effective for example against the
following classes of related phytopathogenic fungi: Fungi
imperfecti (e.g. Botrytis, Pyricularia, Helminthosporium, Fusarium,
Septoria, Cercospora and Alternaria); Basidiomycetes (e.g.
Rhizoctonia, Hemileia, Puccinia); Ascomycetes (e.g. Venturia and
Erysiphe, Podosphaera, Monilinia, Uncinula) and Oomycetes (e.g.
Phylophthora, Pythium, Plasmopara).
[0153] Target crops for the plant-protecting usage in terms of the
invention are for example the following plant cultivars: cereals
(wheat, barley, rye, oats, rice, maize, sorghum and related
species); beet (sugar beet and fodder beet); pome, stone and berry
fruit (apples, pears, plums, peaches, almonds, cherries,
strawberries, raspberries and blackberries); legumes (beans,
lentils, peas, soya); oil crops (rape, mustard, poppy, olives,
sunflowers, coconut, castor oil, cocoa, peanut); cucumber plants
(squashes, cucumber, melons); citrus fruits (oranges, lemons,
grapefruits, mandarines); vegetables (spinach, lettuce, asparagus,
cabbage varieties, carrots, onions, tomatoes, potatoes, paprika);
laurels (avocado, cinnamonium, camphor) and plants such as tobacco,
nuts, coffee, aubergines, sugar cane, tea, pepper, vines, hops,
bananas and natural rubber plants, as well as ornamental
plants.
[0154] Further areas of application for the active ingredients
according to the invention are the protection of stores and
material, where the storage matter is protected against putrescence
and mould.
[0155] The compounds I are used in unchanged form or preferably
together with customary excipients in formulation techniques. To
this end, they are conveniently processed in known manner e.g. into
emulsion concentrates, coatable pastes, directly sprayable or
diluable solutions, diluted emulsions, wettable powders, soluble
powders, dusts or granules, e.g. by encapsulation into for example
polymeric materials. As with the type of medium, the application
processes, such as spraying, atomizing, dusting, scattering,
coating or pouring are similarly chosen according to the desired
aims and the prevailing conditions.
[0156] Suitable substrates and additives may be solid or liquid and
are useful substances in formulation techniques, e.g. natural or
regenerated mineral substances, dissolving aids, dispersants,
wetting agents, tackifiers, thickeners or binding agents.
[0157] The compounds of formula I may be mixed with further active
ingredients, e.g. fertilizers, ingredients providing trace elements
or other active ingredients used in the plant protection science,
especially further fungicides. In doing so, in some cases
synergistic enhancement of the biological effects may occur.
[0158] Preferred active ingredients advantageous as additives to
the compositions comprising the active ingredient of formula I
are:
[0159] Azoles, such as azaconazole, BAY 14120, bitertanol,
bromuconazole, cyproconazole, difenoconazole, diniconazole,
epoxiconazole, fenbuconazole, fluquinconazole, flusilazole,
flutriafol, hexaconazole, imazalil, imibenconazole, ipconazole,
metconazole, myclobutanil, pefurazoate, penconazole, pyrifenox,
prochloraz, propiconazole, simeconazole, tebuconazole,
tetraconazole, triadimefon, triadimenol, triflumizole,
triticonazole; pyrimidinyl carbinoles, such as ancymidol,
fenarimol, nuarimol; 2-amino-pyrimidines, such as bupirimate,
dimethirimol, ethirimol; morpholines, such as dodemorph,
fenpropidine, fenpropimorph, spiroxamine, tridemorph;
anilinopyrimidines, such as cyprodinil, mepanipyrim, pyrimethanil;
pyrroles, such as fenpiclonil, fludioxonil; phenylamides, such as
benalaxyl, furalaxyl, metalaxyl, R-metalaxyl, ofurace, oxadixyl;
benzimidazoles, such as benomyl, carbendazim, debacarb,
fuberidazole, thiabendazole; dicarboximides, such as chlozolinate,
dichlozoline, iprodione, myclozoline, procymidone, vinclozoline;
carboxamides, such as carboxin, fenfuram, flutolanil, mepronil,
oxycarboxin, thifluzamide; guanidines, such as guazatine, dodine,
iminoctadine; strobilurines, such as azoxystrobin, kresoxim-methyl,
metominostrobin, SSF-129, trifloxystrobin, picoxystrobin, BAS 500F
(proposed name pyraclostrobin), BAS 520; dithiocarbamates, such as
ferbam, mancozeb, maneb, metiram, propineb, thiram, zineb, ziram;
N-halomethylthiotetrahydrophthalimides, such as captafol, captan,
dichlofluanid, fluorornides, folpet, tolyfluanid; Cu-compounds,
such as Bordeaux mixture, copper hydroxide, copper oxychloride,
copper sulfate, cuprous oxide, mancopper, oxine-copper;
nitrophenol-derivatives, such as dinocap, nitrothal-isopropyl;
organo-p-derivatives, such as edifenphos, iprobenphos,
isoprothiolane, phosdiphen, pyrazophos, tolclofos-methyl; various
others, such as acibenzolar-S-methyl, anilazine, benthiavalicarb,
blasticidin-S, chinomethionate, chloroneb, chlorothalonil,
cyflufenamid, cymoxanil, dichlone, diclomezine, dicloran,
diethofencarb, dimethomorph, SYP-LI90 (proposed name: flumorph),
dithianon, ethaboxam, etridiazole, famoxadone, fenamidone,
fenoxanil, fentin, ferimzone, fluazinam, flusulfamide, fenhexamid,
fosetyl-aluminium, hymexazol, iprovalicarb, IKF-916 (cyazofamid),
kasugamycin, methasulfocarb, metrafenone, nicobifen, pencycuron,
phthalide, polyoxins, probenazole, propamocarb, pyroquilon,
quinoxyfen, quintozene, sulfur, triazoxide, tricyclazole,
triforine, validamycin, zoxamide (RH7281).
[0160] One preferred method of application of an active ingredient
of formula I or of an agrochemical composition containing at least
one of these active ingredients is foliar application. The
frequency and amount of application depend on the severity of the
attack by the pathogen in question. However, the active ingredients
I may also reach the plants through the root system via the soil
(systemic action) by drenching the locus of the plant with a liquid
preparation or by incorporating the substances into the soil in
solid form, e.g. in the form of granules (soil application). In
rice cultivations, these granules may be dispensed over the flooded
paddy field. The compounds I may however also be applied to seed
grain to treat seed material (coating), whereby the grains or
tubers are either drenched in a liquid preparation of the active
ingredient or coated with a solid preparation.
[0161] The compositions are produced in known manner, e.g. by
intimately mixing and/or grinding the active ingredient with
extenders such as solvents, solid carriers and optionally
surfactants.
[0162] Favorable application rates are in general 1 g to 2 kg of
active substance (AS) per hectare (ha), preferably 10 g to 1 kg
AS/ha, especially 20 g to 600 g AS/ha. For usage as a seed
dressing, it is advantageous to use dosages of 10 mg to 1 g active
substance per kg of seed grain.
[0163] While concentrated compositions are preferred for commercial
usage, the end user normally uses diluted compositions.
[0164] Formulations may be prepared analogously to those described
for example in WO 97/33890.
EXAMPLES
[0165] The subsequent examples are intended to illustrate the
invention, without however limiting the scope thereof.
Synthesis Example 1
N-{4-[2-(1-Dimethylamino-ethylimino)-4-phenyl-thiazol-5-yl]-pyrimidin-2-yl-
}-N-phenyl-amine
[0166] 13
[0167] a) 2-(2-Methylthio-pyrimidin-4-yl) 1-phenyl-ethanone 14
[0168] A mixture of 4-methyl-2-methylthio-pyrimidine (30 g, 0.21
mol) and methyl benzoate (30 g, 0.21 mol) is added to a solution of
potassium tert-butoxide (54 g, 0.48 mol) in tetrahydrofuran (350
ml) with cooling in such a way that the reaction temperature does
not exceed +20.degree. C. After stirring the mixture for additional
20 minutes the solution is poured onto crushed ice. The resulting
solution is acidified with concentrated hydrochloric acid and
extracted with ethyl acetate. Drying of the organic phase,
filtering and evaporation of the solvent under reduced pressure
gives the 2-(2-methylthio-pyrimidin-4-yl)-1-phenyl-ethan- one in
form of a mixture of tautomers.
[0169] b) 2-Bromo-2-(2-methylthio-primidin-4-yl)-1-phenyl-ethanone
15
[0170] Bromine (24.1 g, 0.15 mol) is added with stirring to
2-(2-methylthio-pyrimidin-4-yl)-1-phenyl-ethanone (36.8 g, 0.15
mol) in acetic acid (300 ml) in such a way that the reaction
temperature does not exceed +25.degree. C. and the color of the
bromine is discharged immediately. After the addition of the
bromine solution the solvent is removed by evaporation under
vacuum. The pH of the resulting oil is adjusted to 8 using an
aqueous saturated sodium bicarbonate solution and the product is
extracted several times with diethylther. Drying the combined
extracts with magnesium sulfate, filtering and evaporation of the
solvent gives the crude
2-bromo-2-(2-methylthio-pyrimidin-4-yl)-1-phe- nyl-ethanone in form
of an oil of sufficient purity for the following step.
[0171] c) 4-(2-Amino4-phenyl-thiazol-5-yl)-2-methylthio-pyrimidine
16
[0172] A solution of
2-bromo-2-(2-methylthio-pyrimidin-4-yl)-1-phenyl-etha- none (45 g,
0.14 mol) and thiourea (21.2 g, 0.28 mol) in ethanol (300 ml) is
heated at reflux for 4 hours. On cooling the product starts to
crystallize as salt. It is filtered with suction and washed with
ether. The free amine is obtained by partitioning of the product
between an aqueous solution of sodium bicarbonate and a 1:1 mixture
of ethyl acetate and tetrahydrofuran, followed by drying of the
organic phase over magnesium sulfate, filtering and evaporation of
the solvents. The
4-(2-amino-4-phenyl-thiazol-5-yl)-2-methylthio-pyrimidine is
obtained in crystalline form, m.p. 208-209.degree. C.
[0173] d)
4-(2-Amino-4-phenyl-thiazol-5-yl)-2-methylsulfinvl-pyrimidine
17
[0174] A suspension of
4-(2-amino-4-phenyl-thiazol-5-yl)-2-methylthio-pyri- midine (16.5
g, 0.055 mol) in methylene chloride (350 ml) is cooled to 0.degree.
C. After the addition of m-chloro perbenzoic acid (14.9 g, content
of 70% peracid, 0.06 mol) in 5 portions the resulting solution is
stirred for an additional hour. The reaction mixture is neutralized
by addition of a saturated aqueous solution of sodium bicarbonate
yielding a crystalline suspension of the product. After addition of
hexane the precipitated
4-(2-amino-4-phenyl-thiazol-5-yl)-2-methylsulfinyl-pyrimidin- e is
filtered with suction, washed with water and diethyl ether and
finally dried at +50.degree. C. under high vacuum.
[0175] e)
N-[4-(2-Amino-4-phenyl-thiazol-5-yl)-pyrimidin-2-yl]-N-phenyl-am-
ine 18
[0176] A mixture of
4-(2-amino-4-phenyl-thiazol-5-yl)-2-methylsulfinyl-pyr- imidine
(0.5 g, 1.58 mmol) and aniline (1.5 g, 15.8 mmol) is heated at
+100.degree. C. After the addition of boron trifluoride diethyl
etherate (3 drops) the solution is heated at +150.degree. C. for
half an hour. On cooling the product starts to crystallize. The
crystals are filtered and washed thoroughly with diethyl ether to
give the N-[4-(2-amino-4-phenyl-t-
hiazol-5-yl)-pyrimidin-2-yl]-N-phenyl-amine in pure form, having a
m.p. of 244-245.degree. C.
[0177] f) A suspension of
[4-(2-amino-4-phenyl-thiazol-5-yl)-pyrimidin-2-y- l]-phenyl-amnine
(0.28 g, 0.81 mmol) in dimethylacetamide dimethylacetal (0.22 g,
1.62 mmol) and dimethylformamide (10 ml) is heated at 140.degree.
C. for 4 hours. After distilling off all volatile compounds the
residue is purified by chromatography on silicagel (eluent: ethyl
acetate/hexane) to give in form of a yellow powder, m.p.
196-197.degree. C.
Synthesis Example 2
N-[4-(2-Acetylamino-4-phenyl-thiazol-5-yl)-pyrimidin-2-yl]-N
phenyl-amnine
[0178] 19
[0179] A suspension of
N-[4-(2-amino-4-phenyl-thiazol-5-yl)-pyrimidin-2-yl-
]-N-phenyl-amine (0.25 g, 0.7 mmol), acetic acid anhydride (0.11
mg, 1.1 mmol), triethylamine (0.11 mg, 1.1 mmol) and a catalytic
amount of N,N-dimethylaminopyridine is heated at reflux for 18
hours. The volatiles are evaporated under reduced pressure and the
product is crystallized by the addition of diethyl ether. Filtering
and drying gives the
N-[4-(2-acetylamino-4-phenyl-thiazol-5-yl)-pyrimidin-2-yl]-N-phenyl-amine-
, m.p. >260.degree. C.
Synthesis Example 3
N-{4-[2-(3-Methylbutyl-amino)-4-phenyl-thiazol-5-yl]-pyrimidin-2-yl}-N-phe-
nyl-amine
[0180] 20
[0181] Sodium cyanoborohydride (92 mg, 1.3 mmol) is added at room
temperature to a suspension of
N-[4-(2-amino-4-phenyl-thiazol-5-yl)-pyrim-
idin-2-yl]-N-phenyl-amine (150 mg, 0.4 mmol) and
isovalerianaldehyde (113 mg, 1.3 mmol) in a mixture of methanol (13
ml), acetic acid (0.3 ml) and water (0.05 ml). The reaction mixture
is stirred at room temperature for 18 hours. Partitioning of the
mixture between water and ethyl acetate, drying over magnesium
sulfate, filtering and evaporating of the solvents under reduced
pressure gives the crude product. After crystallization from a
mixture of diethyl ether and hexane the N-{4-[2-(3-methylbutyl-ami-
no)4-phenyl-thiazol-5-yl]-pyrimidin-2-yl}-N-phenyl-amine has a m.p.
of 170-172.degree. C.
Synthesis Example 4
N-[4-(2-Amino4-phenyl-thiazol-5-yl)-primidin-2-yl]-N-[3-(3-hydroxy-3-methy-
l-1-butynyl)-phenyl]-amine
[0182] 21
[0183] a)
N-[4-(2-Amino4-phenyl-thiazol-5-yl)-pyrimidin-2-yl]-N-(3-iodo-ph-
enyl)-amine 22
[0184] A mixture of
5-(2-methylsulfinyl-pyrimidin-4-yl)-4-phenyl-2-amino-t- hiazole
(2.0 g, 6.3 mmol) and m-iodoaniline (7.0 g, 31.6 mmol) is heated at
+100.degree. C. After the addition of boron trifluoride diethyl
etherate (3 drops) the solution is heated at +150.degree. C. for
half an hour. On cooling the product starts to crystallize. The
N-[4(2-amino-4-phenyl-thiazol-5-yl)-pyrimidin-2-yl]-N-(3-iodo-phenyl)-ami-
ne after chromatography (eluent: 2:1 mixture of ethyl
acetate/hexane) has a m.p. of 243-244.degree. C.
[0185] b) A suspension of
N-[4-(2-amino-4-phenyl-thiazol-5-yl)-pyrimidin-2-
-yl]-N-(3-iodo-phenyl)-amine (300 mg, 0.64 mmol) and
2-methyl-3-butyn-2-ol (110 mg, 1.3 mmol) in dimethylformamide (20
ml) and diisopropylamine (5 ml) are stirred in the presence of bis
triphenylphosphine palladiumdichloride (20 mg), triphenylphosphine
(20 mg) and copper iodide under a nitrogen atmosphere for 16 hours.
After an aqueous work-up the residue is purified by chromatography
(eluent: 1:2 mixture of ethyl acetate/hexane) to give the
N-[4-(2-amino-4-phenyl-thiazol-5-yl)-pyrimidi-
n-2-yl]-N-[3-(3-hydroxy-3-methyl-1-butynyl)-phenyl]-amine, m.p.
262-263.degree. C.
Synthesis Example 5
N-[4-(2-Amino-4:phenyl-thiazol-5-yl)-pyrimidin-2-yl]-N-(3',4'-dimethoxy-bi-
phenyl-3-yl)-amine
[0186] 23
[0187] A solution of
N-[4-(2-amino-4-phenyl-thiazol-5-yl)-pyrimidin-2-yl]--
N-(3-iodo-phenyl)-amine (300 mg, 0.64 mmol) and
3,4-dimethoxyphenylboronic acid (122 mg, 0.66 mmol) in
dimethoxyethane (8 ml) and aqueous potassium carbonate (13 ml) are
stirred in the presence of tetrakis triphenylphosphine palladium
(15 mg) under a nitrogen atmosphere at reflux for 1 hour. After an
aqueous work-up the residue is purified by chromatography (eluent:
2:1 mixture of ethyl acetate/hexane) to give the
N-[4-(2-amino-4-phenyl-thiazol-5-yl)-pyrimidin-2-yl]-N-(3',4'-dimethoxy-b-
iphenyl-3-yl)-amine, m.p. 236-237.degree. C.
Synthesis Example 6
N-[4-(2-Amino-4-phenyl-thiazol-5-yl)-pyrimidin-2-yl]-N-[3-(2-hydroxy-2-met-
hyl-ethyl)-phenyl]-amine
[0188] 24
[0189] a)
N-[4-(2-Amino4-phenyl-thiazol-5-yl)-pyrimidin-2-yl]-N-(3-methoxy-
carbonyl-phenyl)-amine
[0190] A mixture of
2-amino-4-phenyl-5-(2-methylsulfinyl-pyrimidin-4-yl)-t- hiazole
(2.0 g, 6.3 mmol) and m-amino benzoic acid methyl ester (13.0 g,
90mmol) is heated at +100.degree. C. After the addition of boron
trifluoride diethyl etherate (3 drops) the solution is heated at
+150.degree. C. for half an hour. After chromatography (eluent:
ethyl acetate/hexane) the
N-[4-(2-amino-4-phenyl-thiazol-5-yl)-pyrimidin-2-yl]--
N-(3-methoxycarbonyl-phenyl)-amine has a m.p. of 223-225.degree.
C.
[0191] b) To a suspension of
N-[4-(2-amino-4-phenyl-thiazol-5-yl)-pyrimidi-
n-2-yl]-N-(3-methoxycarbonyl-phenyl)-amine (800 mg, 2.0 mmol) in
tetrahydrofuran (30 ml) is added a solution of methyl magnesium
chloride (6 ml of a 20% THF solution) without cooling. The
temperature of the reaction mixture rises to about +45.degree. C.
and the starting material dissolves immediately yielding a yellow
clear solution. After an additional hour the solution is poured
onto crushed ice and ammonium chloride. The colorless precipitate
is filtered and washed with ethyl acetate and tetrahydrofuran. The
organic phases are pooled, dried and concentrated under reduced
pressure. Chromatography of the resulting solid gives the
N-[4-(2-amino-4-phenyl-thiazol-5-yl)-pyrimidin-2-yl]-N-[3-
-(2-hydroxy-2-methyl-ethyl)-phenyl]-amine, m.p. 219-220.degree.
C.
Synthesis Example 7
N-[4-(2-Amino4-phenyl-thiazol-5-yl)-pyrimidin-2-yl]-N-(3-hydroxymethyl-phe-
nyl)-amine
[0192] 25
[0193] To a suspension of
N-[4-(2-amino-4-phenyl-thiazol-5-yl)-pyrimidin-2-
-yl]-N-(3-methoxycarbonyl-phenyl)-amine (800 mg, 2.0 mmol) in
tetrahydrofuran (25 ml) is added a solution of sodium
dihydro-bis(2-methoxyethoxy)aluminate in toluene (3 ml of a 3.5M
solution) without cooling. The temperature of the reaction mixture
rises to about +40.degree. C. and the starting material dissolves
immediately yielding a yellow clear solution. After an additional
hour the solution is poured onto crushed ice and ammonium chloride.
The colorless precipitate is filtered and washed with ethyl acetate
and tetrahydrofuran. The organic phases are pooled, dried and
concentrated under reduced pressure. Chromatography of the
resulting solid gives the
N-[4-(2-amino-4-phenyl-thiazol-5-yl)-pyrimidin-2-yl]-N-(3-hydroxymethyl-p-
henyl)-amine, m.p. 214-215.degree. C.
Synthesis Example 8
N-[4-(2-Amino4-phenyl-thiazol-5-yl)-pyrimidin-2-Yl]-N-phenyl-amine
[0194] 26
[0195] a)
2-[N,N-bis(2,2-Dimethylethoxycarbonyl)]-amino]-4-phenyl-thiazole
27
[0196] 2-Amino-4-phenyl-thiazole (5.0 g, 28.4 mmol) is solved in
200 ml of dry THF and a solution of di-tert-butyl pyrocarbonate
(13.6 g, 62.5 mmol) in THF is slowly (dropwise) added. A catalytic
amount of DMAP is added to the reaction mixture before heating it
to reflux for 12 hours. Work-up: after cooling to +25.degree. C.
the reaction solution is poured on ice, acidified with 2N HCl and
extracted with diethylether. The organic phase is separated, dried
with Na.sub.2SO.sub.4, filtered and the solvent is evaporated. The
residue is purified by chromatography over silica gel (eluent:
PE/EE=20:1). The 2-[N,N-bis(2,2-dimethylethoxycarbonyl)-amino]-4-
-phenyl-thiazole is obtained in form of a highly viscous oil.
[0197] .sup.1H-NMR (CDCl.sub.3): 1.48 (s, 18H, CH.sub.3), 7.18 (s,
1H, H-5), 7.22-7.35 (m, 3H, H-3',4'), 7.79 (d, 2H, H-2')
[0198] b) 2-(2,2-Dimethylethoxycarbonyl-amino)4-phenyl-thiazole
28
[0199] The
2-[N,N-bis(2,2-dimethylethoxycarbonyl)-amino]-4phenyl-thiazole
(10.7 g, 28.4 mmol) is suspended in 100 mL of dry CH.sub.2Cl.sub.2
and 5 equivalents of trifluoroacetic acid are added. The mixture is
stirred at +25.degree. C. while test samples are taken and analyzed
by TLC until no starting material is left.
[0200] Work-up: The reaction mixture is poured into water, basified
with saturated aqueous Na.sub.2CO.sub.3-solution and extracted with
CH.sub.2Cl.sub.2. The organic phases are combined, washed with
saturated aqueous NaHCO.sub.3-solution and saturated brine, dried
with Na.sub.2SO.sub.4. The solvent is evaporated and the residue is
dried in high vacuum. This quantitative obtained crude intermediate
2-[N,N-bis(2,2-dimethylethoxycarbonyl)-amino-4-phenylthiazole is
directly used for the following reaction step.
[0201] Yield: yellow highly viscous residue that builds a foam and
solidifies when the last traces of solvent are evaporated, having a
m.p.: 65-70.degree. C. .sup.1H-NMR (CDCl.sub.3): 1.20 (s, 9H,
C(CH.sub.3).sub.3), 7.04 (s, 1H, H-5), 7.20-7.38 (m, 3H, H-3',4'),
7.70-7.80 (d, 2H, H-2', J.sub.2'3'=20 Hz)
[0202] c)
4-[2-(2,2-Dimethylethoxycarbonyl-amino)-4-phenyl-thiazol-5-yl]-2-
-iodo-pyrimidine 29
[0203] The
2-[N,N-bis(2,2-dimethylethoxycarbonyl)-amino-4-phenyl-thiazole
(0.50 g, 1.89 mmol) is solved under a nitrogen atmosphere in 35 mL
of dry THF. The solution is cooled to -78.degree. C. and a solution
of n-BuLi in hexane (4.16 mmol) is added. The mixture is allowed to
warm to -20.degree. C. and stirred for 1.5 hours at this
temperature. Then the mixture is again cooled to -78.degree. C. and
pre-dried ZnCl.sub.2 (0.28 g, 2.08 mmol) in a small volume of dry
THF is added dropwise at a rate which allows to keep the
temperature of the mixture below -60.degree. C. During the
following 1.5 hours the mixture is warmed to +25.degree. C.,
Pd(PPh.sub.3).sub.4 (0.011 g) and 2,4-diiodopyrimidine (0.63 g,
1.89 mmol) are added. The mixture is heated to reflux for 3
hours.
[0204] Work-up: The reaction mixture is poured on aqueous solution
of EDTA, basified with saturated aqueous Na.sub.2CO.sub.3-solution
and extracted with diethyl ether. The crude
4-[2-(2,2-dimethylethoxycarbonyl--
amino)-4-phenyl-thiazol-5-yl]-2-iodo-pyrimidine is purified by
column chromatography on silica gel (eluent: PE/EE=4:1).
[0205] Yield: brownish crystals; m.p.: 135-138.degree. C.
.sup.1H-NMR (CDCl.sub.3): 1.49 (s, 9H, CH.sub.3), 6.98 (d, 1H,
H-5", J.sub.5"6"=5 Hz), 7.35-7.57 (m, 5H, phenyl), 8.03 (d, 1H,
H-6"), 9.00 (bs, 1H, NH).
[0206] d)
N-{4-[2-(2,2-Dimethylethoxycarbonyl-amino)-4-phenyl-thiazol-5-yl-
]-pyrimidin-2-yl}-N-phenyl-amine 30
[0207] The
4-[2-(2,2-dimethylethoxycarbonyl-amino)-4-phenyl-thiazol-5-yl]--
2-iodo-pyrimidine (0.082 g, 0.17 mmol) is heated to reflux with
aniline (0.032 g, 0.34 mmol) and dry p-toluene sulfonic acid (0.026
g, 0.136 mmol) in dry dioxane for five hours.
[0208] Work-up: after cooling to room temperature the mixture is
concentrated until nearly no solvent is present, poured into water,
basified with saturated aqueous Na.sub.2CO.sub.3-solution and
extracted with ethyl acetate. The combined organic extracts are
washed with brine, dried and the solvent is evaporated. The crude
N-{4-[2-(2,2-dimethylethox-
ycarbonyl-amino)-4-phenyl-thiazol-5-yl]-pyrimidin-2-yl}-N-phenyl-amine
is purified by chromatography (silica gel, PE/EE 4:1)., yield the
pure product as brownish crystals, having the m.p.: 290-292.degree.
C.
[0209] .sup.1H-NMR (DMSO-d.sub.6): 1.55 (s, 9H, CH.sub.3), 6.42 (d,
1H, H-5", J.sub.5"6"=5 Hz), 6.90 (t, 1H, H-4a, J.sub.4a3a=10 Hz),
7.28 (t, 2H, H-3a, J.sub.2a3a=10Hz), 7.40-7.60 (m, 5H, phenyl),
7.73 (d, 2H, H-2a), 8.20 (d, 1H, H-6"), 9.60 (s, 1H, NH), 11.79 (s,
1H, NHCO) .sup.13C-NMR (DMSO-d.sub.6): 27.8 (q, CH.sub.3), 81.7 (s,
C(CH.sub.3).sub.3), 107.8 (d), 118.8 (d), 121.4 (d), 124.9 (s),
128.4 (d, 2C), 128.6 (d, 2C), 128.9 (d), 129.0 (d, 2C), 135.2 (s),
140.3 (s), 150.6 (s), 152.8 (s), 157.8 (d), 158.6 (s), 159.6 (s),
160.6 (s)
[0210] e) The
N-{4-[2-(2,2-dimethylethoxycarbonyl-amino)-4-phenyl-thiazol--
5-yl]-pyrimidin-2-yl}-N-phenyl-amine (0.12 g, 0.27 mmol) is
suspended in 5 mL of dry CH.sub.2Cl.sub.2 and treated with 5
equivalents of trifluoroacetic acid. The reaction mixture is
stirred for 12 hours at +25.degree. C., then poured into water,
basified with saturated aqueous Na.sub.2CO.sub.3-solution and
extracted with ethyl acetate. The combined organic extracts are
concentrated to dryness and the last traces of solvent are
evaporated in high vacuum.
[0211] Yield: pure
N-[4-(2-amino-4-phenyl-thiazol-5-yl)-pyrimidin-2-yl]-N--
phenyl-amine in form of yellow crystals of low solubility having a
m.p. of 247-250.degree. C., .sup.1H-NMR (DMSO-d.sub.6): 6.25 (d,
1H, H-5", J.sub.5"6"=5 Hz), 6.92 (t, 1H, H-4a, J.sub.4a5a=7 Hz),
7.25 (t, 2H, H-3a, J.sub.2a3a=8 Hz), 7.40-7.53 (m, 5H, phenyl),
7.60 (s, 2H, NH.sub.2), 7.73 (d, 2H, H-2a), 8.06 (d, 1H, H-6"),
9.45 (s, 1H, NH). .sup.13C-NMR (DMSO-d.sub.6): 106.8 (d), 118.7 (d,
2C), 119.4 (s), 121.2 (d), 128.3 (d, 2C), 128.5 (d), 128.7 (d, 2C),
128.9 (d, 2C), 135.9 (s), 140.5 (s), 153.3 (s), 157.0 (d), 158.7
(s), 159.5 (s), 169.1 (s)
Synthesis Example 9
N-[4-(2-Amino4-phenyl-thiazol-5-yl)-pyrimidin-2-yl]-N-(3-chloro-phenyl)-am-
ine
[0212] 31
[0213] a)
N-{4-[2-(2,2-Dimethylethoxycarbonyl-amino)-4-(3-chloro-phenyl)-t-
hiazol-5-yl]-pyrimidin-2-yl}-N-phenyl-amine 32
[0214] The
4-[2-(2,2-dimethylethoxycarbonyl-amino)-4-phenyl-thiazol-5-yl]--
2-iodo-pyrimidine (0.20 g, 0.416 mmol) is heated to reflux with
3-chloro-aniline (0.106 g, 0.833 mmol) and dry p-toluene sulfonic
acid (0.064 g, 0.33 mmol) in dry dioxane for five hours.
[0215] Work-up: after cooling to room temperature the mixture is
concentrated until nearly no solvent is present, poured into water,
basified with saturated aqueous Na.sub.2CO.sub.3-solution and
extracted with ethyl acetate. The combined organic extracts are
washed with brine, dried and the solvent is evaporated. The crude
N-{4-[2-(2,2-dimethylethox-
ycarbonyl-amino)-4-(3-chloro-phenyl)-thiazol-5-yl)]-pyrimidin-2-yl}-N-phen-
yl-amine is purified by chromatography (silica gel, PE/EE=2:1).,
yield the pure product as yellow crystals, having the m.p.:
295-298.degree. C.
[0216] .sup.1H-NMR (DMSO-d.sub.6): 1.52 (s, 9H, CH.sub.3), 6.46 (d,
1H, H-5", J.sub.5"6"=5 Hz), 6.97 (d, 1H, H-4a, J.sub.4a5a=10 Hz),
7.29 (t, 1H, H-5a, J.sub.5a6a=10 Hz), 7.40-7.60 (m, 5H, phenyl),
7.63 (d, 1H, H-6a), 8.05 (s, 1H, H-2a), 8.23 (d, 1H, H-6"), 9.85
(s, 1H, NH), 11.80 (s, 1H, NHCO) .sup.13C-NMR (DMSO-d.sub.6): 27.8
(q, CH.sub.3), 81.7 (s, C(CH.sub.3).sub.3), 108.2 (d), 117.0 (d),
117.9 (d), 120.8 (d), 124.7 (s), 128.6 (d, 2C), 128.9 (d, 2C),
130.0 (d), 133.0 (s), 135.1 (s), 141.9 (s), 150.9 (s), 152.8 (s),
157.8 (d), 158.7 (s), 159.3 (s), 160.8 (s).
[0217] b) The
N-{4-[2-(2,2-dimethylethoxycarbonyl-amino)-4-(3-chloro-pheny-
l)-thiazol-5-yl]-pyrimidin-2-yl}-N-phenyl-amine (0.05 g, 0.11 mmol)
is suspended in 5 mL of dry CH.sub.2Cl.sub.2 and treated with 2
equivalents of trifluoroacetic acid. The reaction mixture is
stirred for 48 hours at +25.degree. C., then poured into water,
basified with saturated aqueous Na.sub.2CO.sub.3-solution and
extracted with ethyl acetate. The combined organic extracts are
concentrated to dryness and the last traces of solvent are
evaporated in high vacuum.
[0218] Yield: pure
N-[4-(2-amino-4-phenyl-thiazol-5-yl)-pyrimidin-2-yl]-N--
(3-chloro-phenyl)-amine in form of yellow crystals of low
solubility having a m.p. of 243-245.degree. C. .sup.1H-NMR
(DMSO-d.sub.6): 6.28 (d, 1H, H-5", J.sub.5"6"=5 Hz), 6.97 (d, 1H,
H-4a, J.sub.4a5a=7 Hz), 7.27 (t, 1H, H-5a, J.sub.5a6a=8 Hz),
7.40-7.55 (m, 5H, phenyl), 7.55-7.75 (m, 1H, H-6a), 7.65 (s, 2H,
NH.sub.2), 8.00 (t, 1H, H-2a, long-dist.-J=1 Hz), 8.10 (d, 1H,
H-6"), 9.70 (s, 1H, NH)
Synthesis Example 10
N-[4-(2-Amino4-phenyl-thiazol-5-yl)-pyrimidin-2-yl]-N-(3-fluoro-phenyl)-am-
ine
[0219] 33
[0220] a)
N-{4-[2-(2,2-Dimethylethoxycarbonyl-amino)-4-(3-fluoro-phenyl)-t-
hiazol-5-yl]-pyrimidin-2-yl}-N-phenyl-amine 34
[0221] The
4-[-2-(2,2-dimethylethoxycarbonyl-amino)-4-phenyl-thiazol-5-yl]-
-2-iodo-pyrimidine (0.40 g, 0.83 mmol) is heated to reflux with
3-fluoro-aniline (0.185 g, 1.66 mmol) and dry p-toluene sulfonic
acid (0.127 g, 0.66 mmol) in dry dioxane for four hours.
[0222] Work-up: after cooling to room temperature the mixture is
concentrated until nearly no solvent is present, poured into water,
basified with saturated aqueous Na.sub.2CO.sub.3-solution and
extracted with ethyl acetate. The combined organic extracts are
washed with brine, dried and the solvent is evaporated. The crude
N-{4-[2-(2,2-dimethylethox-
ycarbonyl-amino)-4-(3-fluoro-phenyl)-thiazol-5-yl)]-pyrimidin-2-yl}-N-phen-
yl-amine is purified by chromatography (silica gel, PE/EE=2:1).,
yield the pure product as brownish crystals, having the m.p.:
294-297.degree. C. .sup.1H-NMR (DMSO-d.sub.6): 1.52 (s, 9H,
CH.sub.3), 6.48 (d, 1H, H-5", J.sub.5"6"=5 Hz), 6.78 (t, 1H, H-4a,
J.sub.4a5a=10 Hz, J.sub.4aF=10 Hz), 7.30 (q, 1H, H-5a,
J.sub.5a6a=10 Hz, J.sub.5aF=10 Hz), 7.40-7.60 (m, 6H, phenyl,
H-6a), 7.82 (dt, 1H, H-2a, J.sub.2aF=14 Hz, long-dist.-J=2 Hz),
8.25 (d, 1H, H-6"), 9.85 (s, 1H, NH), 11.80 (s, 1H, NHCO).
.sup.13C-NMR (DMSO-d.sub.6): 27.8 (q, CH.sub.3), 81.7 (s,
C(CH.sub.3).sub.3), 105.2 (dd, C-2a, J.sub.2aF=27 Hz), 107.5 (dd,
C-4a, J.sub.4aF=21 Hz), 108.3 (d), 114.4 (d, C-6a), 124.7 (s),
128.6 (d, 2C), 129.0 (d, 2C), 129.7 (d), 129.9 (d), 135.1 (s),
142.2 (d, C-1a, J.sub.1aF=11 Hz), 150.9 (s), 152.8 (s), 157.8 (d),
158.7 (s), 159.4 (s), 160.8 (s), 162.3 (d, C-3a, J.sub.3aF=240
Hz)
[0223] b) The
N-{4-[2-(2,2-dimethylethoxycarbonyl-amino)-4-(3-fluoro-pheny-
l)-thiazol-5-yl]-pyrimidin-2-yl}-N-phenyl-amine (0.05 g, 0.11 mmol)
is suspended in 5 mL of dry CH.sub.2Cl.sub.2 and treated with 5
equivalents of trifluoroacetic acid. The reaction mixture is
stirred for 12 hours at +25.degree. C., then poured into water,
basified with saturated aqueous Na.sub.2CO.sub.3-solution and
extracted with ethyl acetate. The combined organic extracts are
concentrated to dryness and the last traces of solvent are
evaporated in high vacuum.
[0224] Yield: pure
N-[4-(2-amino-4-phenyl-thiazol-5-yl)-pyrimidin-2-yl]-N--
(3-fluoro-phenyl)-amine in form of yellow crystals of low
solubility having a m.p. of 243-245.degree. C. .sup.1H-NMR
(DMSO-d.sub.6): 6.31 (d, 1H, H-5", J.sub.5"6"=5 Hz), 6.75 (t, 1H,
H-4a, J.sub.4a5a=8 Hz, J.sub.4aF=8 Hz), 7.28 (q, 1H, H-5a,
J.sub.5a6a=8 Hz, J.sub.5aF=8 Hz), 7.38-7.60 (m, 6H, phenyl, H-6a),
7.19 (s, 2H, NH.sub.2), 7.83 (d, 1H, H-2a, J.sub.2aF=12 Hz), 8.12
(d, 1H, H-6"), 9.23 (s, 1H, NH) .sup.13C-NMR (DMSO-d.sub.6): 105.1
(dd, J.sub.CF=27 Hz), 107.3 (dd, J.sub.CF=21 Hz), 107.4 (d), 114.4
(d), 119.2 (s), 128.6 (d, 2C), 128.8 (d, C-4'), 128.9 (d, 2C),
129.8 (dd, C-5a, J.sub.5aF=10 Hz), 135.9 (s), 142.4 (d, C-1a,
J.sub.1aF=11 Hz), 153.7 (s), 157.0 (d), 158.8 (s), 159.3 (s), 162.4
(d, C-3a, J.sub.3aF=240 Hz), 169.2 (s, C-2).
Synthesis Example 11
N-[4-(2-Amino-4-phenyl-thiazol-5-yl)-pyrimidin-2-yl]-N-(3-methoxy-phenyl)--
amine
[0225] 35
[0226] The
4-[2-(2,2-dimethylethoxycarbonyl-amino)-4-phenyl-thiazol-5-yl]--
2-iodo-pyrimidine (1.0 g, 2.1 mmol) is heated to reflux with
3-methoxy-aniline (0.32 g, 0.29 mL) and p-toluene sulfonic
acid-mono hydrate (0.34 g, 1.8 mmol) in dioxane for four hours.
[0227] Work-up: when TLC-control indicates quantitative conversion
(but still 2-spots at R.sub.f=0.23 and 0.09, PE/EE 2:1) and after
cooling to room temperature the mixture is concentrated until
nearly no solvent is present, poured into a mixture ethyl acetate
and water, basified with saturated aqueous
Na.sub.2CO.sub.3-solution and extracted with ethyl acetate. The
combined organic extracts are dried with Na.sub.2SO.sub.4 and the
solvent is evaporated. 0.87 g of a brown residue remains. According
to NMR-check this raw product contains about 67% of the desired
N-[4-(2-amino-4-phenyl-thiazol-5-yl)-pyrimidin-2-yl]-N-(3-methoxy-phenyl)-
-amine and a more polar product. The amount necessary for the NMR
is easily solved in CDCl.sub.3 while larger quantities of are
difficult to solve in CHCl.sub.3, ethyl acetate or DMSO, whereby
the desired title product resolves easier than the main by-product.
The raw product-mixture is digerated with a small quantity of
CHCl.sub.3 in order to separate it from the darkly colored
impurities. The CHCl.sub.3-phase which contains most of the title
product is decanted rapidly. 100 mg of the so-obtained
raw-product-mixture is stirred in 1 ml of TFA/CH.sub.2Cl.sub.2
(1:1) for 12 hours.
[0228] Work-up: TLC control of the solution reveals only one spot
at R.sub.f=0.09. The reaction solution is transferred to a
separation funnel with ethyl acetate, neutralized with saturated
aqueous NaHCO.sub.3-solution and extracted with ethyl acetate. The
combined organic phase is dried with Na.sub.2SO.sub.4 and the
solvent is evaporated. The pure
N-[4-(2-amino-4-phenyl-thiazol-5-yl)-pyrimidin-2-yl]-
-N-(3-methoxy-phenyl)-amine is obtained as yellow crystals in
quantitative yield having a m.p. of 115-117.degree. C. .sup.1H-NMR
(DMSO-d.sub.6); 3.76 (s, 3H, CH.sub.3), 6.24 (d, 1H, H-5",
J.sub.5"6"=5 Hz), 6.52 (d, 1H, J=8 Hz), 7.14 (t, 1H, J=8 Hz), 7.29
(d, 1H, J=8 Hz), 7.40-7.55 (m, 6H, phenyl+1H), 7.63 (s, 2H,
NH.sub.2), 8.06 (d, 1H, H-6"), 8.10 (d, 1H, H-6"), 9.44 (s, 1H,
NH).
Synthesis Example 12
N-{4-[2-(4-Methylpiperazin-1-yl)-4-phenyl-thiazol-5-yl]-pyrimidin-2-yl}]-N-
-phenyl-amine
[0229] 36
[0230] a)
4-(2-Chloro-4-phenyl-thiazol-5-yl)-2-methylsulfinyl-pyrimidine
37
[0231] To a suspension of copper-II-chloride (3.2 g, 23.5 mmol) and
t-butylnitrite (2.9 g, 27.5 mmol) in acetonitrile (300 ml) is added
4-(2-amino-4-phenyl-thiazol-5-yl)-2-methylsulfinyl-pyrimidine (6.2
g, 19.6 mmol) in small portions at room temperature. After stirring
for three hours at room temperature the reaction mixture is diluted
with ethyl acetate and washed repeatedly with water. Drying over
magnesium sulfate, filtering, evaporating the solvents and
purification by chromatography gives the
4-(2-chloro-4-phenyl-thiazol-5-yl)-2-methylsulfi- nyl-pyrimidine as
a yellow colored solid.
[0232] b)
4-[2-(4-Methylpiperazin-1-yl)-4-phenyl-thiazol-5-yl]-2-methylsul-
finyl-pyrimidine 38
[0233] A solution of N-methylpiperazine (0.6 g, 6.0 mmol) in
tetrahydrofuran (5 ml) is added to a well stirred solution of
4-(2-chloro-4-phenyl-thiazol-5-yl)-2-methylsulfinyl-pyrimidine (1.0
g,3.0 mmol) in tetrahydrofuran (20 ml) at +5.degree. C. The
reaction mixture is allowed to warm to room temperature over night.
Evaporation of the solvent leaves a crystalline residue that is
suspended in water, filtered with suction, washed with diethyl
ether and dried under vacuum. The product
4-[2-(4-methylpiperazin-1-yl)-4-phenyl-thiazol-5-yl]-2-methylsulf-
inyl-pyrimidine shows a m.p. of 166-169.degree. C.
[0234] c) A mixture of
4-[2-(4-methylpiperazin-1-yl)-4-phenyl-thiazol-5-yl-
]-2-methylsulfinyl-pyrimidine (0.5 g, 1.25 mmol) and aniline (1.5
g, 15.8mmol) is heated at +100.degree. C. After the addition of
boron trifluoride diethyl etherate (3 drops) the solution is heated
at +150.degree. C. for half an hour. After the reaction mixture is
cooled to room temperature water and diethylether is added
sequentially to precipitate the product. The crystals are filtered
and washed thoroughly with diethyl ether to give the
N-{4-[2-(4-methylpiperazin-1-yl)4-phenyl-t-
hiazol-5-yl]-pyrimidin-2-yl}]-N-phenyl-amine in pure form, having a
m.p. of 239-240.degree. C.
[0235] Using analogous procedures to the above described working
examples the compounds of the following tables may be obtained.
1TABLE 01 Compounds of the general structure I.01, wherein each
individual species corresponds to the combination of the
definitions R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, und
R.sub.6 of the lines of table A. (I.01) 39
[0236]
2TABLE 02 Compounds of the general structure I.02, wherein each
individual species corresponds to the combination of the
definitions R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, und
R.sub.6 of the lines of table A. (I.02) 40
[0237]
3TABLE 03 Compounds of the general structure I.03, wherein each
individual species corresponds to the combination of the
definitions R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, und
R.sub.6 of the lines of table A. (I.03) 41
[0238]
4TABLE 04 Compounds of the general structure I.04, wherein each
individual species corresponds to the combination of the
definitions R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, und
R.sub.6 of the lines of table A. (I.04) 42
[0239]
5TABLE 05 Compounds of the general structure I.05, wherein each
individual species corresponds to the combination of the
definitions R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, und
R.sub.6 of the lines of table A. (I.05) 43
[0240]
6TABLE 06 Compounds of the general structure I.06, wherein each
individual species corresponds to the combination of the
definitions R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, und
R.sub.6 of the lines of table A. (I.06) 44
[0241]
7TABLE 07 Compounds of the general structure I.07, wherein each
individual species corresponds to the combination of the
definitions R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, and
R.sub.6 of the lines of table A. 45 (I.07)
[0242]
8TABLE 08 Compounds of the general structure I.08, wherein each
individual species corresponds to the combination of the
definitions R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, und
R.sub.6 of the lines of table A. (I.08) 46
[0243]
9TABLE 09 Compounds of the general structure I.09, wherein each
individual species corresponds to the combination of the
definitions R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, und
R.sub.6 of the lines of table A. (I.09) 47
[0244]
10TABLE 10 Compounds of the general structure I.10, wherein each
individual species corresponds to the combination of the
definitions R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, und
R.sub.6 of the lines of table A. (I.10) 48
[0245]
11TABLE A Comp- No. R.sub.1 R.sub.2 R.sub.3 R.sub.4 R.sub.5 R.sub.6
0001 H H H --CH.sub.2--O--CH.sub.3 H H 0002 H H H
--NH--CO--CH.sub.3 H H 0003 H H H --CH.sub.2--NH--CO--CH.sub.3 H H
0004 H H H --CH(CH.sub.3)--NH--CO--CH.sub.3 H H 0005 H H H
--C(CH.sub.3).sub.2--NH--CO--CH.sub.3 H H 0006 H H H
--CH(CH.sub.3)--O--CH.sub.3 H H 0007 H H H --C(CH.sub.3).sub.2--O--
-CH.sub.3 H H 0008 H H H --CH(CH.sub.3)--O--CO--CH.sub.3 H H 0009 H
H H --CH.sub.2--O--CO--CH.sub.3 H H 0010 H H H
--C(CH.sub.3).sub.2--O--CO--CH.sub.3 H H 0011 H H H
--CH.sub.2--CH.sub.2--O--H H H 0012 H H H --CH.sub.2--CH.sub.2--O--
-CH.sub.3 H H 0013 H H H 49 H H 0014 H H H 50 H H 0015 H H H 51 H H
0016 H H H 52 H H 0017 H H H 53 H H 0018 H H H 54 H H 0019 H H H 55
H H 0020 H H H 56 H H 0021 H H H 57 H H 0022 H H H 58 H H 0023 H H
H 59 H H 0024 H H H 60 H H 0025 H H H H H H 0026 H H H CN H H 0027
H H H --C(CH.sub.3).sub.2--OH H H 0028 H H H --CH.sub.2--OH H H
0029 H H H --CO--CH.sub.3 H H 0030 H H H --C(.dbd.NOH)--CH.sub.3 H
H 0031 H H H --CH(OH)--CH.sub.3 H H 0032 H H H (3)
--CO--O--CH.sub.2-- (4) H 0033 H H H --CH.sub.2--CN H H 0034 H H H
--C(.dbd.NO--CH.sub.3)--CH.sub.3 H H 0035 H H H --CO--O--CH.sub.3 H
H 0036 H H H --NH--CO--C.sub.3H.sub.5-cycl. H H 0037 H H H
--CO--CH.sub.3 Cl H 0038 H H H --OH H H 0039 H H H --OH --OCH.sub.3
H 0040 H H H --OCH.sub.3 H --OCH.sub.3 0041 H H H --SCH.sub.3 H H
0042 H H H --OCH.sub.3 H H 0043 H H H --OCH.sub.3 --OCH.sub.3
--OCH.sub.3 0044 H H H --OH --OCH.sub.3 --OCH.sub.3 0045 H H H H
--SCH.sub.3 H 0046 H H --OCH.sub.3 H --OCH.sub.3 H 0047 H H H
--OCH.sub.3 --OH H 0048 H H --OCH.sub.3 H H H 0049 H H H
--CH.sub.2--CH.sub.3 H H 0050 H H --OCH.sub.3 --CH(CH.sub.3).sub.2
H H 0051 H H H --C.sub.3H.sub.7-n H H 0052 H H H
--OCH.sub.2--CH.sub.3 H H 0053 H H H Cl H H 0054 H H H Br H H 0055
H H H Cl Cl H 0056 H H H OH OH OH 0057 H H Cl Cl H Cl 0058 H H H
--CF.sub.3 H H 0059 H H H --OCF.sub.3 H H 0060 H H H
--C.sub.2F.sub.5 H H 0061 H H H --C.sub.4H.sub.9-tert H H 0062 H H
H --OC.sub.3H.sub.7-i H H 0063 H H H CH.sub.3 H H 0064 H H H
--SO.sub.2--CH.sub.3 H H 0065 H H H --NH--CH.sub.2--CH.sub.3 H H
0066 H H H --O--CH.sub.2--CH.dbd.CH.s- ub.2 H H 0067 H H H
--O--CH.sub.2--C.dbd.CH H H 0068 H H H
--NH--CH.sub.2--CH.sub.2--NH--CH.sub.3 H H 0069 H H H
--SO.sub.2--C.sub.2H.sub.5 H H 0070 H H H --SO.sub.2--CH.sub.3 Cl H
0071 C.sub.2H.sub.5 H H --CH.sub.2--O--CH.sub.3 H H 0072
C.sub.2H.sub.5 H H --NH--CO--CH.sub.3 H H 0073 C.sub.2H.sub.5 H H
--CH.sub.2--NH--CO--CH.sub.3 H H 0074 C.sub.2H.sub.5 H H
--CH(CH.sub.3)--NH--CO--CH.sub.3 H H 0075 C.sub.2H.sub.5 H H
--C(CH.sub.3).sub.2--NH--CO--CH.sub.3 H H 0076 C.sub.2H.sub.5 H H
--CH(CH.sub.3)--O--CH.sub.3 H H 0077 C.sub.2H.sub.5 H H
--C(CH.sub.3).sub.2--O--CH.sub.3 H H 0078 C.sub.2H.sub.5 H H
--CH(CH.sub.3)--O--CO--CH.sub.3 H H 0079 C.sub.2H.sub.5 H H
--CH.sub.2--O--CO--CH.sub.3 H H 0080 C.sub.2H.sub.5 H H
--C(CH.sub.3).sub.2--O--CO--CH.sub.3 H H 0081 C.sub.2H.sub.5 H H
--CH.sub.2--CH.sub.2--O--H H H 0082 C.sub.2H.sub.5 H H
--CH.sub.2--CH.sub.2--O--CH.sub.3 H H 0083 C.sub.2H.sub.5 H H 61 H
H 0084 C.sub.2H.sub.5 H H 62 H H 0085 C.sub.2H.sub.5 H H 63 H H
0086 C.sub.2H.sub.5 H H 64 H H 0087 C.sub.2H.sub.5 H H 65 H H 0088
C.sub.2H.sub.5 H H 66 H H 0089 C.sub.2H.sub.5 H H 67 H H 0090
C.sub.2H.sub.5 H H 68 H H 0091 C.sub.2H.sub.5 H H 69 H H 0092
C.sub.2H.sub.5 H H 70 H H 0093 C.sub.2H.sub.5 H H 71 H H 0094
C.sub.2H.sub.5 H H 72 H H 0095 C.sub.2H.sub.5 H H H H H 0096
C.sub.2H.sub.5 H H CN H H 0097 C.sub.2H.sub.5 H H
--C(CH.sub.3).sub.2--OH H H 0098 C.sub.2H.sub.5 H H --CH.sub.2--OH
H H 0099 C.sub.2H.sub.5 H H --CO--CH.sub.3 H H 0100 C.sub.2H.sub.5
H H --C(.dbd.NOH)--CH.sub.3 H H 0101 C.sub.2H.sub.5 H H
--CH(OH)--CH.sub.3 H H 0102 C.sub.2H.sub.5 H H (3)
--CO--O--CH.sub.2-- (4) H 0103 C.sub.2H.sub.5 H H
--CH.sub.2--O--CO--CH.sub.3 H H 0104 C.sub.2H.sub.5 H H
--C(.dbd.NO--CH.sub.3)--CH.sub.3 H H 0105 C.sub.2H.sub.5 H H
--CO--O--CH.sub.3 H H 0106 C.sub.2H.sub.5 H H
--NH--CO--C.sub.3H.sub.5-cycl. H H 0107 C.sub.2H.sub.5 H H
--CO--CH.sub.3 Cl H 0108 C.sub.2H.sub.5 H H --OH H H 0109
C.sub.2H.sub.5 H H --OH --OCH.sub.3 H 0110 C.sub.2H.sub.5 H H
--OCH.sub.3 H --OCH.sub.3 0111 C.sub.2H.sub.5 H H --SCH.sub.3 H H
0112 C.sub.2H.sub.5 H H --OCH.sub.3 H H 0113 C.sub.2H.sub.5 H H
--OCH.sub.3 --OCH.sub.3 --OCH.sub.3 0114 C.sub.2H.sub.5 H H --OH
--OCH.sub.3 --OCH.sub.3 0115 C.sub.2H.sub.5 H H H --SCH.sub.3 H
0116 C.sub.2H.sub.5 H H H --OCH.sub.3 H 0117 C.sub.2H.sub.5 H H
--OCH.sub.3 --OH H 0118 C.sub.2H.sub.5 H --OCH.sub.3 --CH.sub.3 H H
0119 C.sub.2H.sub.5 H H --CH.sub.2--CH.sub.3 H H 0120
C.sub.2H.sub.5 H --OCH.sub.3 --CH(CH.sub.3).sub.2 H H 0121
C.sub.2H.sub.5 H H --C.sub.3H.sub.7-n H H 0122 C.sub.2H.sub.5 H H
--OCH.sub.2--CH.sub.3 H H 0123 C.sub.2H.sub.5 H H F H H 0124
C.sub.2H.sub.5 H H Cl H H 0125 C.sub.2H.sub.5 H H Br H H 0126
C.sub.2H.sub.5 H H Cl Cl H 0127 C.sub.2H.sub.5 H H OH OH OH 0128
C.sub.2H.sub.5 H Cl Cl H Cl 0129 C.sub.2H.sub.5 H H --CF.sub.3 H H
0130 C.sub.2H.sub.5 H H --OCF.sub.3 H H 0131 C.sub.2H.sub.5 H H
--C.sub.2F.sub.5 H H 0132 C.sub.2H.sub.5 H H --C.sub.4H.sub.9-tert
H H 0133 C.sub.2H.sub.5 H H --OC.sub.3H.sub.7-i H H 0134
C.sub.2H.sub.5 H H --SO--C.sub.3 H H 0135 C.sub.2H.sub.5 H H
--SO.sub.2--CH.sub.3 H H 0136 C.sub.2H.sub.5 H H
--NH--CH.sub.2--CH.sub.3 H H 0137 C.sub.2H.sub.5 H H
--O--CH.sub.2--CH.dbd.CH.sub.2 H H 0138 C.sub.2H.sub.5 H H
--O--CH.sub.2--C.dbd.CH H H 0139 C.sub.2H.sub.5 H H
--NH--CH.sub.2--CH.sub.2--NH--CH.sub.3 H H 0140 C.sub.2H.sub.5 H H
--SO.sub.2--C.sub.2H.sub.5 H H 0141 C.sub.2H.sub.5 H H
--SO.sub.2--CH.sub.3 Cl H 0142 CH.sub.3 H H --CH.sub.2--O--CH.sub.3
H H 0143 CH.sub.3 H H --NH--CO--CH.sub.3 H H 0144 CH.sub.3 H H
--CH.sub.2--NH--CO--CH.sub.3 H H 0145 CH.sub.3 H H
--CH(CH.sub.3)--NH--CO--CH.sub.3 H H 0146 CH.sub.3 H H
--C(CH.sub.3).sub.2--NH--CO--CH.sub.3 H H 0147 CH.sub.3 H H
--CH(CH.sub.3)--O--CH.sub.3 H H 0148 CH.sub.3 H H
--C(CH.sub.3).sub.2--O--CH.sub.3 H H 0149 CH.sub.3 H H
--CH(CH.sub.3)--O--CO--CH.sub.3 H H 0150 CH.sub.3 H H
--CH.sub.2--O--CO--CH.sub.3 H H 0151 CH.sub.3 H H
--C(CH.sub.3).sub.2--O--CO--CH.sub.3 H H 0152 CH.sub.3 H H
--CH.sub.2--CH.sub.2--O--H H H 0153 CH.sub.3 H H 73 H H 0154
CH.sub.3 H H 74 H H 0155 CH.sub.3 H H 75 H H 0156 CH.sub.3 H H 76 H
H 0157 CH.sub.3 H H 77 H H 0158 CH.sub.3 H H 78 H H 0159 CH.sub.3 H
H 79 H H 0160 CH.sub.3 H H 80 H H 0161 CH.sub.3 H H 81 H H 0162
CH.sub.3 H H 82 H H 0163 CH.sub.3 H H 83 H H 0164 CH.sub.3 H H 84 H
H 0165 CH.sub.3 H H H H H 0166 CH.sub.3 H H CN H H 0167 CH.sub.3 H
H --C(CH.sub.3).sub.2--OH H H 0168 CH.sub.3 H H --CH.sub.2--OH H H
0169 CH.sub.3 H H --CO--CH.sub.3 H H 0170 CH.sub.3 H H
--C(.dbd.NOH)--CH.sub.3 H H 0171 CH.sub.3 H H --CH(OH)--CH.sub.3 H
H 0172 CH.sub.3 H H (3) --CO--O--CH.sub.2-- (4) H 0173 CH.sub.3 H H
--CH.sub.2--O--CO--CH.sub.3 H H 0174 CH.sub.3 H H
--C(.dbd.NO--CH.sub.3)--CH.sub.3 H H 0175 CH.sub.3 H H
--CO--O--CH.sub.3 H H 0176 CH.sub.3 H H --NH--CO--C.sub.3H.sub.5-c-
ycl. H H 0177 CH.sub.3 H H --CO--CH.sub.3 Cl H 0178 CH.sub.3 H H
--OH H H 0179 CH.sub.3 H H --OH --OCH.sub.3 H 0180 CH.sub.3 H H
--OCH.sub.3 H --OCH.sub.3 0181 CH.sub.3 H H --SCH.sub.3 H H 0182
CH.sub.3 H H --OCH.sub.3 H H 0183 CH.sub.3 H H --OCH.sub.3
--OCH.sub.3 --OCH.sub.3 0184 CH.sub.3 H H --OH --OCH.sub.3
--OCH.sub.3 0185 CH.sub.3 H H H --SCH.sub.3 H 0186 CH.sub.3 H H H
--OCH.sub.3 H 0187 CH.sub.3 H H --OCH.sub.3 --OH H 0188 CH.sub.3 H
--OCH.sub.3 --CH.sub.3 H H 0189 CH.sub.3 H H --CH.sub.2--CH.sub.3 H
H 0190 CH.sub.3 H --OCH.sub.3 --CH(CH.sub.3).sub.2 H H 0191
CH.sub.3 H H --C.sub.3H.sub.7-n H H 0192 CH.sub.3 H H
--OCH.sub.2--CH.sub.3 H H 0193 CH.sub.3 H H F H H 0194 CH.sub.3 H H
Cl H H 0195 CH.sub.3 H H Br H H 0196 CH.sub.3 H H Cl Cl H 0197
CH.sub.3 H H OH OH OH 0198 CH.sub.3 H Cl Cl H Cl 0199 CH.sub.3 H H
--CF.sub.3 H H 0200 H H H --OCH.sub.2--CF.sub.3 H H 0201 CH.sub.3 H
H --C.sub.2F.sub.5 H H 0202 CH.sub.3 H H --C.sub.4H.sub.9-tert H H
0203 CH.sub.3 H H --OC.sub.3H.sub.7-i H H 0204 CH.sub.3 H H
--SO--CH.sub.3 H H 0205 CH.sub.3 H H --SO.sub.2--CH.sub.3 H H 0206
CH.sub.3 H H --NH--CH.sub.2--CH.sub.3 H H 0207 CH.sub.3 H H
--O--CH.sub.2--CH.dbd.CH.sub.2 H H 0208 CH.sub.3 H H
--O--CH.sub.2--C.dbd.CH H H 0209 CH.sub.3 H H
--NH--CH.sub.2--CH.sub.2--NH--CH.sub.3 H H 0210 CH.sub.3 H H
--SO.sub.2--C.sub.2H.sub.5 H H 0211 CH.sub.3 H H
--SO.sub.2--CH.sub.3 Cl H 0212 CH.sub.3 CH.sub.3 H
--CH.sub.2--O--CH.sub.3 H H 0213 CH.sub.3 CH.sub.3 H
--NH--CO--CH.sub.3 H H 0214 CH.sub.3 CH.sub.3 H
--CH.sub.2--NH--CO--CH.sub.3 H H 0215 CH.sub.3 CH.sub.3 H
--CH(CH.sub.3)--NH--CO--CH.sub.3 H H 0216 CH.sub.3 CH.sub.3 H
--C(CH.sub.3).sub.2--NH--CO--CH.sub.3 H H 0217 CH.sub.3 CH.sub.3 H
--CH(CH.sub.3)--O--CH.sub.3 H H 0218 CH.sub.3 CH.sub.3 H
--C(CH.sub.3).sub.2--O--CH.sub.3 H H 0219 CH.sub.3 CH.sub.3 H
--CH(CH.sub.3)--O--CO--CH.sub.3 H H 0220 CH.sub.3 CH.sub.3 H
--CH.sub.2--O--CO--CH.sub.3 H H 0221 CH.sub.3 CH.sub.3 H
--C(CH.sub.3).sub.2--O--CO--CH.sub.3 H H 0222 CH.sub.3 CH.sub.3 H
--CH.sub.2--CH.sub.2--O--H H H 0223 CH.sub.3 CH.sub.3 H
--CH.sub.2--CH.sub.2--O--CH.sub.3 H H 0224 CH.sub.3 CH.sub.3 H 85 H
H 0225 CH.sub.3 CH.sub.3 H 86 H H 0226 CH.sub.3 CH.sub.3 H 87 H H
0227 CH.sub.3 CH.sub.3 H 88 H H 0228 CH.sub.3 CH.sub.3 H 89 H H
0229 CH.sub.3 CH.sub.3 H 90 H H 0230 CH.sub.3 CH.sub.3 H 91 H H
0231 CH.sub.3 CH.sub.3 H 92 H H 0232 CH.sub.3 CH.sub.3 H 93 H H
0233 CH.sub.3 CH.sub.3 H 94 H H 0234 CH.sub.3 CH.sub.3 H 95 H H
0235 CH.sub.3 CH.sub.3 H 96 H H 0236 CH.sub.3 CH.sub.3 H H H H 0237
CH.sub.3 CH.sub.3 H CN H H 0238 CH.sub.3 CH.sub.3 H
--C(CH.sub.3).sub.2--OH H H 0239 CH.sub.3 CH.sub.3 H --CH.sub.2--OH
H H 0240 CH.sub.3 CH.sub.3 H --CO--CH.sub.3 H H 0241 CH.sub.3
CH.sub.3 H --C(.dbd.NOH)--CH.sub.3 H H 0242 CH.sub.3 CH.sub.3 H
--CH(OH)--CH.sub.3 H H 0243 CH.sub.3 CH.sub.3 H (3)
--CO--O--CH.sub.2-- (4) H 0244 CH.sub.3 CH.sub.3 H
--CH.sub.2--O--CO--CH.sub.3 H H 0245 CH.sub.3 CH.sub.3 H
--C(.dbd.NO--CH.sub.3)--CH.sub.3 H H 0246 CH.sub.3 CH.sub.3 H
--CO--O--CH.sub.3 H H 0247 CH.sub.3 CH.sub.3 H
--NH--CO--C.sub.3H.sub.5-cycl. H H 0248 CH.sub.3 CH.sub.3 H
--NH--CO--C.sub.6H.sub.11-cycl. H H 0249 CH.sub.3 CH.sub.3 H
--CO--CH.sub.3 Cl H 0250 CH.sub.3 CH.sub.3 H --OH H H 0251 CH.sub.3
CH.sub.3 H --OH --OCH.sub.3 H 0252 CH.sub.3 CH.sub.3 H --OCH.sub.3
H --OCH.sub.3 0253 CH.sub.3 CH.sub.3 H --OCH.sub.3 H H 0254
CH.sub.3 CH.sub.3 H --OCH.sub.3 --OCH.sub.3 --OCH.sub.3 0255
CH.sub.3 CH.sub.3 H --OH --OCH.sub.3 --OCH.sub.3 0256 CH.sub.3
CH.sub.3 H H --SCH.sub.3 H 0257 CH.sub.3 CH.sub.3 H H --OCH.sub.3 H
0258 CH.sub.3 CH.sub.3 H --OCH.sub.3 --OH H 0259 CH.sub.3 CH.sub.3
--OCH.sub.3 --CH.sub.3 H H 0260 CH.sub.3 CH.sub.3 H
--CH.sub.2--CH.sub.3 H H 0261 CH.sub.3 CH.sub.3 --OCH.sub.3
--CH(CH.sub.3).sub.2 H H 0262 CH.sub.3 CH.sub.3 H
--C.sub.3H.sub.7-n H H 0263 CH.sub.3 CH.sub.3 H
--OCH.sub.2--CH.sub.3 H H 0264 CH.sub.3 CH.sub.3 H F H H 0265
CH.sub.3 CH.sub.3 H Cl H H 0266 CH.sub.3 CH.sub.3 H Br H H 0267
CH.sub.3 CH.sub.3 H Cl Cl H 0268 CH.sub.3 CH.sub.3 H OH OH OH 0269
CH.sub.3 CH.sub.3 Cl Cl H Cl 0270 CH.sub.3 CH.sub.3 H --CF.sub.3 H
H 0271 CH.sub.3 CH.sub.3 H --OCF.sub.3 H H 0272 CH.sub.3 CH.sub.3 H
--C.sub.2F.sub.5 H H 0273 CH.sub.3 CH.sub.3 H --C.sub.4H.sub.9-tert
H H 0274 CH.sub.3 CH.sub.3 H --OC.sub.3H.sub.7-i H H 0275 CH.sub.3
CH.sub.3 H --SO--CH.sub.3 H H 0276 CH.sub.3 CH.sub.3 H
--SO.sub.2--CH.sub.3 H H 0277 CH.sub.3 CH.sub.3 H
--NH--CH.sub.2--CH.sub.3 H H 0278 CH.sub.3 CH.sub.3 H
--O--CH.sub.2--CH.dbd.CH.sub.2 H H 0279 CH.sub.3 CH.sub.3 H
--O--CH.sub.2--C.dbd.CH H H 0280 CH.sub.3 CH.sub.3 H
--NH--CH.sub.2--CH.sub.2--NH--CH.sub.3 H H 0281 CH.sub.3 CH.sub.3 H
--SO.sub.2--C.sub.2H.sub.5 H H 0282 CH.sub.3 CH.sub.3 H
--SO.sub.2--CH.sub.3 Cl H 0283 --CO--CH.sub.3 H H
--CH.sub.2--O--CH.sub.3 H H 0284 --CO--CH.sub.3 H H
--NH--CO--CH.sub.3 H H 0285 --CO--CH.sub.3 H H
--CH.sub.2--NH--CO--CH.sub.3 H H 0286 --CO--CH.sub.3 H H
--CH(CH.sub.3)--NH--CO--CH.sub.3 H H 0287 --CO--CH.sub.3 H H
--C(CH.sub.3).sub.2--NH--CO--CH.sub.3 H H 0288 --CO--CH.sub.3 H H
--CH(CH.sub.3)--O--CH.sub.3 H H 0289 --CO--CH.sub.3 H H
--C(CH.sub.3).sub.2--O--CH.sub.3 H H 0290 --CO--CH.sub.3 H H
--CH(CH.sub.3)--O--CO--CH.sub.3 H H 0291 --CO--CH.sub.3 H H
--CH.sub.2--O--CO--CH.sub.3 H H 0292 --CO--CH.sub.3 H H
--C(CH.sub.3).sub.2--O--CO--CH.sub.3 H H 0293 --CO--CH.sub.3 H H
--CH.sub.2--CH.sub.2--O--H H H 0294 --CO--CH.sub.3 H H
--CH.sub.2--CH.sub.2--O--CH.sub.3 H H 0295 --CO--CH.sub.3 H H 97 H
H 0296 --CO--CH.sub.3 H H 98 H H 0297 --CO--CH.sub.3 H H 99 H H
0298 --CO--CH.sub.3 H H 100 H H 0299 --CO--CH.sub.3 H H 101 H H
0300 --CO--CH.sub.3 H H 102 H H 0301 --CO--CH.sub.3 H H 103 H H
0302 --CO--CH.sub.3 H H 104 H H 0303 --CO--CH.sub.3 H H 105 H H
0304 --CO--CH.sub.3 H H 106 H H 0305 --CO--CH.sub.3 H H 107 H H
0306 --CO--CH.sub.3 H H 108 H H 0307 --CO--CH.sub.3 H H H H H 0308
--CO--CH.sub.3 H H CN H H 0309 --CO--CH.sub.3 H H
--C(CH.sub.3).sub.2--OH H H 0310 --CO--CH.sub.3 H H --CH.sub.2--OH
H H 0311 --CO--CH.sub.3 H H --CO--CH.sub.3 H H 0312 --CO--CH.sub.3
H H --C(.dbd.NOH)--CH.sub.3 H H 0313 --CO--CH.sub.3 H H
--CH(OH)--CH.sub.3 H H 0314 --CO--CH.sub.3 H H (3)
--CO--O--CH.sub.2-- (4) H 0315 --CO--CH.sub.3 H H
--CH.sub.2--O--CO--CH.sub.3 H H 0316 --CO--CH.sub.3 H H
--C(.dbd.NO--CH.sub.3)--CH.sub.3 H H 0317 --CO--CH.sub.3 H H
--CO--O--CH.sub.3 H H 0318 --CO--CH.sub.3 H H
--NH--CO--C.sub.3H.sub.5-cycl. H H 0319 --CO--CH.sub.3 H H
--CO--CH.sub.3 Cl H 0320 --CO--CH.sub.3 H H --OH H H 0321
--CO--CH.sub.3 H H --OH --OCH.sub.3 H 0322 --CO--CH.sub.3 H H
--OCH.sub.3 H --OCH.sub.3 0323 --CO--CH.sub.3 H H --SCH.sub.3 H H
0324 --CO--CH.sub.3 H H --OCH.sub.3 H H 0325 --CO--CH.sub.3 H H
--OCH.sub.3 --OCH.sub.3 --OCH.sub.3 0326 --CO--CH.sub.3 H H --OH
--OCH.sub.3 --OCH.sub.3 0327 --CO--CH.sub.3 H H H --SCH.sub.3 H
0328 --CO--CH.sub.3 H H H --OCH.sub.3 H 0329 --CO--CH.sub.3 H H
--OCH.sub.3 --OH H 0330 --CO--CH.sub.3 H --OCH.sub.3 --CH.sub.3 H H
0331 --CO--CH.sub.3 H H --CH.sub.2--CH.sub.3 H H 0332
--CO--CH.sub.3 H --OCH.sub.3 --CH(CH.sub.3).sub.2 H H 0333
--CO--CH.sub.3 H H --C.sub.3H.sub.7-n H H 0334 --CO--CH.sub.3 H H
--OCH.sub.2--CH.sub.3 H H 0335 --CO--CH.sub.3 H H F H H 0336
--CO--CH.sub.3 H H Cl H H 0337 --CO--CH.sub.3 H H Br H H
0338 --CO--CH.sub.3 H H Cl Cl H 0339 --CO--CH.sub.3 H H OH OH OH
0340 --CO--CH.sub.3 H Cl Cl H Cl 0341 --CO--CH.sub.3 H H --CF.sub.3
H H 0342 --CO--CH.sub.3 H H --OCF.sub.3 H H 0343 --CO--CH.sub.3 H H
--C.sub.2F.sub.5 H H 0344 --CO--CH.sub.3 H H --C.sub.4H.sub.9-tert
H H 0345 --CO--CH.sub.3 H H --OC.sub.3H.sub.7-i H H 0346
--CO--CH.sub.3 H H --SO--CH.sub.3 H H 0347 --CO--CH.sub.3 H H
--SO.sub.2--CH.sub.3 H H 0348 --CO--CH.sub.3 H H
--NH--CH.sub.2--CH.sub.3 H H 0349 --CO--CH.sub.3 H H
--O--CH.sub.2--CH.dbd.CH.sub.2 H H 0350 --CO--CH.sub.3 H H
--O--CH.sub.2--C.dbd.CH H H 0351 --CO--CH.sub.3 H H
--NH--CH.sub.2--CH.sub.2--NH --CH.sub.3 H H 0352 --CO--CH.sub.3 H H
--SO.sub.2--C.sub.2H.sub.5 H H 0353 --CO--C.sub.2H.sub.5 H H
--CH.sub.2--O--CH.sub.3 H H 0354 --CO--C.sub.2H.sub.5 H H
--NH--CO--CH.sub.3 H H 0355 --CO--C.sub.2H.sub.5 H H
--CH.sub.2--NH--CO--CH.sub.3 H H 0356 --CO--C.sub.2H.sub.5 H H
--CH(CH.sub.3)--NH--CO--CH.sub.3 H H 0357 --CO--C.sub.2H.sub.5 H H
--C(CH.sub.3).sub.2--NH--CO--CH.sub.3 H H 0358 --CO--C.sub.2H.sub.5
H H --CH(CH.sub.3)--O--CH.sub.3 H H 0359 --CO--C.sub.2H.sub.5 H H
--C(CH.sub.3).sub.2--O--CH.sub.3 H H 0360 --CO--C.sub.2H.sub.5 H H
--CH(CH.sub.3)--O--CO--CH.sub.3 H H 0361 --CO--C.sub.2H.sub.5 H H
--CH.sub.2--O--CO--CH.sub.3 H H 0362 --CO--C.sub.2H.sub.5 H H
--C(CH.sub.3).sub.2--O--CO--CH.sub.3 H H 0363 --CO--C.sub.2H.sub.5
H H --CH.sub.2--CH.sub.2--O--H H H 0364 --CO--C.sub.2H.sub.5 H H
--CH.sub.2--CH.sub.2--O--CH.sub.3 H H 0365 --CO--C.sub.2H.sub.5 H H
109 H H 0366 --CO--C.sub.2H.sub.5 H H 110 H H 0367
--CO--C.sub.2H.sub.5 H H 111 H H 0368 --CO--C.sub.2H.sub.5 H H 112
H H 0369 --CO--C.sub.2H.sub.5 H H 113 H H 0370 --CO--C.sub.2H.sub.5
H H 114 H H 0371 --CO--C.sub.2H.sub.5 H H 115 H H 0372
--CO--C.sub.2H.sub.5 H H 116 H H 0373 --CO--C.sub.2H.sub.5 H H 117
H H 0374 --CO--C.sub.2H.sub.5 H H 118 H H 0375 --CO--C.sub.2H.sub.5
H H 119 H H 0376 --CO--C.sub.2H.sub.5 H H 120 H H 0377
--CO--C.sub.2H.sub.5 H H H H H 0378 --CO--C.sub.2H.sub.5 H H CN H H
0379 --CO--C.sub.2H.sub.5 H H --C(CH.sub.3).sub.2--OH H H 0380
--CO--C.sub.2H.sub.5 H H --CH.sub.2--OH H H 0381
--CO--C.sub.2H.sub.5 H H --CO--CH.sub.3 H H 0382
--CO--C.sub.2H.sub.5 H H --C(.dbd.NOH)--CH.sub.3 H H 0383
--CO--C.sub.2H.sub.5 H H --CH(OH)--CH.sub.3 H H 0384
--CO--C.sub.2H.sub.5 H H (3) --CO--O--CH.sub.2-- (4) H 0385
--CO--C.sub.2H.sub.5 H H --CH.sub.2--O--CO--CH.sub.3 H H 0386
--CO--C.sub.2H.sub.5 H H --C(.dbd.NO--CH.sub.3)--CH.sub.3 H H 0387
--CO--C.sub.2H.sub.5 H H --CO--O--CH.sub.3 H H 0388
--CO--C.sub.2H.sub.5 H H --NH--CO--C.sub.3H.sub.5-cycl. H H 0389
--CO--C.sub.2H.sub.5 H H --CO--CH.sub.3 Cl H 0390
--CO--C.sub.2H.sub.5 H H --OH H H 0391 --CO--C.sub.2H.sub.5 H H
--OH --OCH.sub.3 H 0392 --CO--C.sub.2H.sub.5 H H --OCH.sub.3 H
--OCH.sub.3 0393 --CO--C.sub.2H.sub.5 H H --SCH.sub.3 H H 0394
--CO--C.sub.2H.sub.5 H H --OCH.sub.3 H H 0395 --CO--C.sub.2H.sub.5
H H --OCH.sub.3 --OCH.sub.3 --OCH.sub.3 0396 --CO--C.sub.2H.sub.5 H
H --OH --OCH.sub.3 --OCH.sub.3 0397 --CO--C.sub.2H.sub.5 H H H
--SCH.sub.3 H 0398 --CO--C.sub.2H.sub.5 H H H --OCH.sub.3 H 0399
--CO--C.sub.2H.sub.5 H H --OCH.sub.3 --OH H 0400
--CO--C.sub.2H.sub.5 H --OCH.sub.3 --CH.sub.3 H H 0401
--CO--C.sub.2H.sub.5 H H --CH.sub.2--CH.sub.3 H H 0402
--CO--C.sub.2H.sub.5 H --OCH.sub.3 --CH(CH.sub.3).sub.2 H H 0403
--CO--C.sub.2H.sub.5 H H --C.sub.3H.sub.7-n H H 0404
--CO--C.sub.2H.sub.5 H H --OCH.sub.2--CH.sub.3 H H 0405
--CO--C.sub.2H.sub.5 H H F H H 0406 --CO--C.sub.2H.sub.5 H H Cl H H
0407 --CO--C.sub.2H.sub.5 H H Br H H 0408 --CO--C.sub.2H.sub.5 H H
Cl Cl H 0409 --CO--C.sub.2H.sub.5 H H OH OH OH 0410
--CO--C.sub.2H.sub.5 H Cl Cl H Cl 0411 --CO--C.sub.2H.sub.5 H H
--CF.sub.3 H H 0412 --CO--C.sub.2H.sub.5 H H --OCF.sub.3 H H 0413
--CO--C.sub.2H.sub.5 H H --C.sub.2F.sub.5 H H 0414
--CO--C.sub.2H.sub.5 H H --C.sub.4H.sub.9-tert H H 0415
--CO--C.sub.2H.sub.5 H H --OC.sub.3H.sub.7-i H H 0416
--CO--C.sub.2H.sub.5 H H --SO--CH.sub.3 H H 0417
--CO--C.sub.2H.sub.5 H H --SO.sub.2--CH.sub.3 H H 0418
--CO--C.sub.2H.sub.5 H H --NH--CH.sub.2--CH.sub.3 H H 0419
--CO--C.sub.2H.sub.5 H H --O--CH.sub.2--CH.dbd.CH.sub.2 H H 0420
--CO--C.sub.2H.sub.5 H H --O--CH.sub.2--C.dbd.CH H H 0421
--CO--C.sub.2H.sub.5 H H --NH--CH.sub.2--CH.sub.2--NH--CH.sub.3 H H
0422 --CO--C.sub.2H.sub.5 H H --SO.sub.2--C.sub.2H.sub.5 H H 0423
--CO--C.sub.2H.sub.5 H H --SO.sub.2--CH.sub.3 Cl H 0424
--CO--CH(CH.sub.3)--C.sub.2H.sub.5 H H --CH.sub.2--O--CH.sub.3 H H
0425 --CO--CH(CH.sub.3)--C.sub.2H.sub.5 H H --NH--CO--CH.sub.3 H H
0426 --CO--CH(CH.sub.3)--C.sub.2H.sub.5 H H
--CH.sub.2--NH--CO--CH.sub.3 H H 0427
--CO--CH(CH.sub.3)--C.sub.2H.sub.5 H H
--CH(CH.sub.3)--NH--CO--CH.sub.3 H H 0428 --CO--CH(CH.sub.3)--C.su-
b.2H.sub.5 H H --C(CH.sub.3).sub.2--NH--CO--CH.sub.3 H H 0429
--CO--CH(CH.sub.3)--C.sub.2H.sub.5 H H --CH(CH.sub.3)--O--CH.sub.3
H H 0430 --CO--CH(CH.sub.3)--C.sub.2H.sub.5 H H
--C(CH.sub.3).sub.2--O--C- H.sub.3 H H 0431
--CO--CH(CH.sub.3)--C.sub.2H.sub.5 H H
--CH(CH.sub.3)--O--CO--CH.sub.3 H H 0432 --CO--CH(CH.sub.3)--C.sub-
.2H.sub.5 H H --CH.sub.2--O--CO--CH.sub.3 H H 0433
--CO--CH(CH.sub.3)--C.sub.2H.sub.5 H H
--C(CH.sub.3).sub.2--O--CO--CH.sub- .3 H H 0434
--CO--CH(CH.sub.3)--C.sub.2H.sub.5 H H --CH.sub.2--CH.sub.2--O--H H
H 0435 --CO--CH(CH.sub.3)--C.sub.2H.s- ub.5 H H
--CH.sub.2--CH.sub.2--O--CH.sub.3 H H 0436
--CO--CH(CH.sub.3)--C.sub.2H.sub.5 H H 121 H H 0437
--CO--CH(CH.sub.3)--C.sub.2H.sub.5 H H 122 H H 0438
--CO--CH(CH.sub.3)--C.sub.2H.sub.5 H H 123 H H 0439
--CO--CH(CH.sub.3)--C.sub.2H.sub.5 H H 124 H H 0440
--CO--CH(CH.sub.3)--C.sub.2H.sub.5 H H 125 H H 0441
--CO--CH(CH.sub.3)--C.sub.2H.sub.5 H H 126 H H 0442
--CO--CH(CH.sub.3)--C.sub.2H.sub.5 H H 127 H H 0443
--CO--CH(CH.sub.3)--C.sub.2H.sub.5 H H 128 H H 0444
--CO--CH(CH.sub.3)--C.sub.2H.sub.5 H H 129 H H 0445
--CO--CH(CH.sub.3)--C.sub.2H.sub.5 H H 130 H H 0446
--CO--CH(CH.sub.3)--C.sub.2H.sub.5 H H 131 H H 0447
--CO--CH(CH.sub.3)--C.sub.2H.sub.5 H H 132 H H 0448
--CO--CH(CH.sub.3)--C.sub.2H.sub.5 H H H H H 0449
--CO--CH(CH.sub.3)--C.sub.2H.sub.5 H H CN H H 0450
--CO--CH(CH.sub.3)--C.sub.2H.sub.5 H H --C(CH.sub.3).sub.2--OH H H
0451 --CO--CH(CH.sub.3)--C.sub.2H.sub.5 H H --CH.sub.2--OH H H 0452
--CO--CH(CH.sub.3)--C.sub.2H.sub.5 H H --CO--CH.sub.3 H H 0453
--CO--CH(CH.sub.3)--C.sub.2H.sub.5 H H --CH(OH)--CH.sub.3 H H 0454
--CO--CH(CH.sub.3)--C.sub.2H.sub.5 H H (3) --CO--O--CH.sub.2-- (4)
H 0455 --CO--CH(CH.sub.3)--C.sub.2H.sub.5 H H
--CH.sub.2--O--CO--CH.sub.3 H H 0456 --CO--CH(CH.sub.3)--C.sub.2H.-
sub.5 H H --C(.dbd.NO--CH.sub.3)--CH.sub.3 H H 0457
--CO--CH(CH.sub.3)--C.sub.2H.sub.5 H H --CO--O--CH.sub.3 H H 0458
--CO--CH(CH.sub.3)--C.sub.2H.sub.5 H H
--NH--CO--C.sub.3H.sub.5-cycl. H H 0459
--CO--CH(CH.sub.3)--C.sub.2H.sub.5 H H --CO--CH.sub.3 Cl H 0460
--CO--CH(CH.sub.3)--C.sub.2H.sub.5 H H --OH H H 0461
--CO--CH(CH.sub.3)--C.sub.2H.sub.5 H H --OH --OCH.sub.3 H 0462
--CO--CH(CH.sub.3)--C.sub.2H.sub.5 H H --OCH.sub.3 H --OCH.sub.3
0463 --CO--CH(CH.sub.3)--C.sub.2H.sub.5 H H --SCH.sub.3 H H 0464
--CO--CH(CH.sub.3)--C.sub.2H.sub.5 H H --OCH.sub.3 H H 0465
--CO--CH(CH.sub.3)--C.sub.2H.sub.5 H H --OCH.sub.3 --OCH.sub.3
--OCH.sub.3 0466 --CO--CH(CH.sub.3)--C.sub.2H.sub.5 H H --OH
--OCH.sub.3 --OCH.sub.3 0467 --CO--CH(CH.sub.3)--C.sub.2H.sub.5 H H
H --SCH.sub.3 H 0468 --CO--CH(CH.sub.3)--C.sub.2H.sub.5 H H H
--OCH.sub.3 H 0469 --CO--CH(CH.sub.3)--C.sub.2H.sub.5 H H
--OCH.sub.3 --OH H 0470 --CO--CH(CH.sub.3)--C.sub.2H.sub.5 H
--OCH.sub.3 --CH.sub.3 H H 0471 --CO--CH(CH.sub.3)--C.sub.2H.sub.5
H H --CH.sub.2--CH.sub.3 H H 0472 --CO--CH(CH.sub.3)--C.sub.2H.sub-
.5 H --OCH.sub.3 --CH(CH.sub.3).sub.2 H H 0473
--CO--CH(CH.sub.3)--C.sub.2H.sub.5 H H --C.sub.3H.sub.7-n H H 0474
--CO--CH(CH.sub.3)--C.sub.2H.sub.5 H H --OCH.sub.2--CH.sub.3 H H
0475 --CO--CH(CH.sub.3)--C.sub.2H.sub.5 H H F H H 0476
--CO--CH(CH.sub.3)--C.sub.2H.sub.5 H H Cl H H 0477
--CO--CH(CH.sub.3)--C.sub.2H.sub.5 H H Br H H 0478
--CO--CH(CH.sub.3)--C.sub.2H.sub.5 H H Cl Cl H 0479
--CO--CH(CH.sub.3)--C.sub.2H.sub.5 H H OH OH OH 0480
--CO--CH(CH.sub.3)--C.sub.2H.sub.5 H Cl Cl H Cl 0481
--CO--CH(CH.sub.3)--C.sub.2H.sub.5 H H --CF.sub.3 H H 0482
--CO--CH(CH.sub.3)--C.sub.2H.sub.5 H H --OCF.sub.3 H H 0483
--CO--CH(CH.sub.3)--C.sub.2H.sub.5 H H --C.sub.2F.sub.5 H H 0484
--CO--CH(CH.sub.3)--C.sub.2H.sub.5 H H --C.sub.4H.sub.9-tert H H
0485 --CO--CH(CH.sub.3)--C.sub.2H.sub.5 H H --OC.sub.3H.sub.7-i H H
0486 --CO--CH(CH.sub.3)--C.sub.2H.sub.5 H H --SO--CH.sub.3 H H 0487
--CO--CH(CH.sub.3)--C.sub.2H.sub.5 H H --SO.sub.2--CH.sub.3 H H
0488 --CO--CH(CH.sub.3)--C.sub.2H.sub.5 H H
--NH--CH.sub.2--CH.sub.3 H H 0489
--CO--CH(CH.sub.3)--C.sub.2H.sub.5 H H
--O--CH.sub.2--CH.dbd.CH.sub.2 H H 0490 --CO--CH(CH.sub.3)--C.sub.-
2H.sub.5 H H --O--CH.sub.2--C.dbd.CH H H 0491
--CO--CH(CH.sub.3)--C.sub.2H.sub.5 H H
--NH--CH.sub.2--CH.sub.2--NH--CH.s- ub.3 H H 0492
--CO--CH(CH.sub.3)--C.sub.2H.sub.5 H H --SO.sub.2--C.sub.2H.sub.5 H
H 0493 --CO--CH(CH.sub.3)--C.sub.2H.s- ub.5 H H
--SO.sub.2--CH.sub.3 Cl H 0494 --CO--C.sub.3F.sub.7-n H H
--CH.sub.2--O--CH.sub.3 H H 0495 --CO--C.sub.3F.sub.7-n H H
--NH--CO--CH.sub.3 H H 0496 --CO--C.sub.3F.sub.7-n H H
--CH.sub.2--NH--CO--CH.sub.3 H H 0497 --CO--C.sub.3F.sub.7-n H H
--CH(CH.sub.3)--NH--CO--CH.sub.3 H H 0498 --CO--C.sub.3F.sub.7-n H
H --C(CH.sub.3).sub.2--NH--CO--CH.sub.3 H H 0499
--CO--C.sub.3F.sub.7-n H H --CH(CH.sub.3)--O--CH.sub.3 H H 0500
--CO--C.sub.3F.sub.7-n H H --C(CH.sub.3).sub.2--O--CH.sub.3 H H
0501 --CO--C.sub.3F.sub.7-n H H --CH(CH.sub.3)--O--CO--CH.sub.3 H H
0502 --CO--C.sub.3F.sub.7-n H H --CH.sub.2--O--CO--CH.sub.3 H H
0503 --CO--C.sub.3F.sub.7-n H H
--C(CH.sub.3).sub.2--O--CO--CH.sub.3 H H 0504
--CO--C.sub.3F.sub.7-n H H --CH.sub.2--CH.sub.2--O--H H H 0505
--CO--C.sub.3F.sub.7-n H H --CH.sub.2--CH.sub.2--O--CH.sub.3 H H
0506 --CO--C.sub.3F.sub.7-n H H 133 H H 0507 --CO--C.sub.3F.sub.7-n
H H 134 H H 0508 --CO--C.sub.3F.sub.7-n H H 135 H H 0509
--CO--C.sub.3F.sub.7-n H H 136 H H 0510 --CO--C.sub.3F.sub.7-n H H
137 H H 0511 --CO--C.sub.3F.sub.7-n H H 138 H H 0512
--CO--C.sub.3F.sub.7-n H H 139 H H 0513 --CO--C.sub.3F.sub.7-n H H
140 H H 0514 --CO--C.sub.3F.sub.7-n H H 141 H H 0515
--CO--C.sub.3F.sub.7-n H H 142 H H 0516 --CO--C.sub.3F.sub.7-n H H
143 H H 0517 --CO--C.sub.3F.sub.7-n H H 144 H H 0518
--CO--C.sub.3F.sub.7-n H H H H H 0519 --CO--C.sub.3F.sub.7-n H H CN
H H 0520 --CO--C.sub.3F.sub.7-n H H --C(CH.sub.3).sub.2--OH H H
0521 --CO--C.sub.3F.sub.7-n H H --CH.sub.2--OH H H 0522
--CO--C.sub.3F.sub.7-n H H --CO--CH.sub.3 H H 0523
--CO--C.sub.3F.sub.7-n H H --C(.dbd.NOH)--CH.sub.3 H H 0524
--CO--C.sub.3F.sub.7-n H H --CH(OH)--CH.sub.3 H H 0525
--CO--C.sub.3F.sub.7-n H H (3) --CO--O--CH.sub.2-- (4) H 0526
--CO--C.sub.3F.sub.7-n H H --CH.sub.2--O--CO--CH.sub.3 H H 0527
--CO--C.sub.3F.sub.7-n H H --C(.dbd.NO--CH.sub.3)--CH.sub.3 H H
0528 --CO--C.sub.3F.sub.7-n H H --CO--O--CH.sub.3 H H 0529
--CO--C.sub.3F.sub.7-n H H --NH--CO--C.sub.3H.sub.5-cycl. H H 0530
--CO--C.sub.3F.sub.7-n H H --CO--CH.sub.3 Cl H 0531
--CO--C.sub.3F.sub.7-n H H --OH H H 0532 --CO--C.sub.3F.sub.7-n H H
--OH --OCH.sub.3 H 0533 --CO--C.sub.3F.sub.7-n H H --OCH.sub.3 H
--OCH.sub.3 0534 --CO--C.sub.3F.sub.7-n H H --SCH.sub.3 H H 0535
--CO--C.sub.3F.sub.7-n H H --OCH.sub.3 H H 0536
--CO--C.sub.3F.sub.7-n H H --OCH.sub.3 --OCH.sub.3 --OCH.sub.3 0537
--CO--C.sub.3F.sub.7-n H H --OH --OCH.sub.3 --OCH.sub.3 0538
--CO--C.sub.3F.sub.7-n H H H --SCH.sub.3 H 0539
--CO--C.sub.3F.sub.7-n H H H --OCH.sub.3 H 0540
--CO--C.sub.3F.sub.7-n H H --OCH.sub.3 --OH H 0541
--CO--C.sub.3F.sub.7-n H --OCH.sub.3 --CH.sub.3 H H 0542
--CO--C.sub.3F.sub.7-n H H --CH.sub.2--CH.sub.3 H H 0543
--CO--C.sub.3F.sub.7-n H --OCH.sub.3 --CH(CH.sub.3).sub.2 H H 0544
--CO--C.sub.3F.sub.7-n H H --C.sub.3H.sub.7-n H H 0545
--CO--C.sub.3F.sub.7-n H H --OCH.sub.2--CH.sub.3 H H 0546
--CO--C.sub.3F.sub.7-n H H F H H 0547 --CO--C.sub.3F.sub.7-u H H Cl
H H 0548 --CO--C.sub.3F.sub.7-n H H Br H H 0549
--CO--C.sub.3F.sub.7-n H H Cl Cl H 0550 --CO--C.sub.3F.sub.7-n H H
OH OH OH 0551 --CO--C.sub.3F.sub.7-n H Cl Cl H Cl 0552
--CO--C.sub.3F.sub.7-n H H --CF.sub.3 H H 0553
--CO--C.sub.3F.sub.7-n H H --C.sub.2F.sub.5 H H 0554
--CO--C.sub.3F.sub.7-n H H --C.sub.4H.sub.9-tert H H 0555
--CO--C.sub.3F.sub.7-n H H --OC.sub.3H.sub.7-i H H 0556
--CO--C.sub.3F.sub.7-n H H --SO--CH.sub.3 H H 0557
--CO--C.sub.3F.sub.7-n H H --SO.sub.2--CH.sub.3 H H 0558
--CO--C.sub.3F.sub.7-n H H --NH--CH.sub.2--CH.sub.3 H H 0559
--CO--C.sub.3F.sub.7-n H H --O--CH.sub.2--CH.dbd.CH.sub.2 H H 0560
--CO--C.sub.3F.sub.7-n H H --O--CH.sub.2--C.dbd.CH H H 0561
--CO--C.sub.3F.sub.7-n H H --NH--CH.sub.2--CH.sub.2--NH--CH.sub.3 H
H 0562 --CO--C.sub.3F.sub.7-n H H --SO.sub.2--C.sub.2H.sub.5 H H
0563 --CO--C.sub.3F.sub.7-n H H --SO.sub.2--CH.sub.3 Cl H 0564
--CO--CH.sub.2--O--CO--CH.sub.3 H H --CH.sub.2--O--CH.sub.3 H H
0565 --CO--CH.sub.2--O--CO--CH.sub.3 H H --NH--CO--CH.sub.3 H H
0566 --CO--CH.sub.2--O--CO--CH.sub.3 H H
--CH.sub.2--NH--CO--CH.sub.3 H H 0567
--CO--CH.sub.2--O--CO--CH.sub.3 H H --CH(CH.sub.3)--NH--CO--C-
H.sub.3 H H 0568 --CO--CH.sub.2--O--CO--CH.sub.3 H H
--C(CH.sub.3).sub.2--NH--CO--CH.sub.3 H H 0569
--CO--CH.sub.2--O--CO--CH.sub.3 H H --CH(CH.sub.3)--O--CH.sub.3 H H
0570 --CO--CH.sub.2--O--CO--CH.sub.3 H H
--C(CH.sub.3).sub.2--O--CH.sub.- 3 H H 0571
--CO--CH.sub.2--O--CO--CH.sub.3 H H --CH(CH.sub.3)--O--CO--CH.sub.3
H H 0572 --CO--CH.sub.2--O--CO--CH- .sub.3 H H
--CH.sub.2--O--CO--CH.sub.3 H H 0573
--CO--CH.sub.2--O--CO--CH.sub.3 H H
--C(CH.sub.3).sub.2--O--CO--CH.sub.3 H H 0574
--CO--CH.sub.2--O--CO--CH.sub.3 H H --CH.sub.2--CH.sub.2--O--H H H
0575 --CO--CH.sub.2--O--CO--CH.sub.- 3 H H
--CH.sub.2--CH.sub.2--O--CH.sub.3 H H 0576
--CO--CH.sub.2--O--CO--CH.sub.3 H H 145 H H 0577
--CO--CH.sub.2--O--CO--CH.sub.3 H H 146 H H 0578
--CO--CH.sub.2--O--CO--CH.sub.3 H H 147 H H 0579
--CO--CH.sub.2--O--CO--CH.sub.3 H H 148 H H 0580
--CO--CH.sub.2--O--CO--CH.sub.3 H H 149 H H 0581
--CO--CH.sub.2--O--CO--CH.sub.3 H H 150 H H 0582
--CO--CH.sub.2--O--CO--CH.sub.3 H H 151 H H 0583
--CO--CH.sub.2--O--CO--CH.sub.3 H H 152 H H 0584
--CO--CH.sub.2--O--CO--CH.sub.3 H H 153 H H 0585
--CO--CH.sub.2--O--CO--CH.sub.3 H H 154 H H 0586
--CO--CH.sub.2--O--CO--CH.sub.3 H H 155 H H 0587
--CO--CH.sub.2--O--CO--CH.sub.3 H H 156 H H 0588
--CO--CH.sub.2--O--CO--CH.sub.3 H H H H H 0589
--CO--CH.sub.2--O--CO--CH.sub.3 H H CN H H 0590
--CO--CH.sub.2--O--CO--CH.sub.3 H H --C(CH.sub.3).sub.2--OH H H
0591 --CO--CH.sub.2--O--CO--CH.sub.3 H H --CH.sub.2--OH H H
0592
--CO--CH.sub.2--O--CO--CH.sub.3 H H --CO--CH.sub.3 H H 0593
--CO--CH.sub.2--O--CO--CH.sub.3 H H --C(.dbd.NOH)--CH.sub.3 H H
0594 --CO--CH.sub.2--O--CO--CH.sub.3 H H --CH(OH)--CH.sub.3 H H
0595 --CO--CH.sub.2--O--CO--CH.sub.3 H H (3) --CO--O--CH.sub.2--
(4) H 0596 --CO--CH.sub.2--O--CO--CH.sub.3 H H
--CH.sub.2--O--CO--CH.sub.3 H H 0597
--CO--CH.sub.2--O--CO--CH.sub.3 H H
--C(.dbd.NO--CH.sub.3)--CH.sub.3 H H 0598 --CO--CH.sub.2--O--CO--C-
H.sub.3 H H --CO--O--CH.sub.3 H H 0599
--CO--CH.sub.2--O--CO--CH.su- b.3 H H
--NH--CO--C.sub.3H.sub.5-cycl. H H 0600
--CO--CH.sub.2--O--CO--CH.sub.3 H H --CO--CH.sub.3 Cl H 0601
--CO--CH.sub.2--O--CO--CH.sub.3 H H --OH H H 0602
--CO--CH.sub.2--O--CO--CH.sub.3 H H --OH --OCH.sub.3 H 0603
--CO--CH.sub.2--O--CO--CH.sub.3 H H --OCH.sub.3 H --OCH.sub.3 0604
--CO--CH.sub.2--O--CO--CH.sub.3 H H --SCH.sub.3 H H 0605
--CO--CH.sub.2--O--CO--CH.sub.3 H H --OCH.sub.3 H H 0606
--CO--CH.sub.2--O--CO--CH.sub.3 H H --OCH.sub.3 --OCH.sub.3
--OCH.sub.3 0607 --CO--CH.sub.2--O--CO--CH.sub.3 H H --OH
--OCH.sub.3 --OCH.sub.3 0608 --CO--CH.sub.2--O--CO--CH.sub.3 H H H
--SCH.sub.3 H 0609 --CO--CH.sub.2--O--CO--CH.sub.3 H H H
--OCH.sub.3 H 0610 --CO--CH.sub.2--O--CO--CH.sub.3 H H --OCH.sub.3
--OH H 0611 --CO--CH.sub.2--O--CO--CH.sub.3 H --OCH.sub.3
--CH.sub.3 H H 0612 --CO--CH.sub.2--O--CO--CH.sub.3 H H
--CH.sub.2--CH.sub.3 H H 0613 --CO--CH.sub.2--O--CO--CH.sub.3 H
--OCH.sub.3 --CH(CH.sub.3).sub.2 H H 0614
--CO--CH.sub.2--O--CO--CH.sub.3 H H --C.sub.3H.sub.7-n H H 0615
--CO--CH.sub.2--O--CO--CH.sub.3 H H --OCH.sub.2--CH.sub.3 H H 0616
--CO--CH.sub.2--O--CO--CH.sub.3 H H F H H 0617
--CO--CH.sub.2--O--CO--CH.sub.3 H H Cl H H 0618
--CO--CH.sub.2--O--CO--CH.sub.3 H H Br H H 0619
--CO--CH.sub.2--O--CO--CH.sub.3 H H Cl Cl H 0620
--CO--CH.sub.2--O--CO--CH.sub.3 H H OH OH OH 0621
--CO--CH.sub.2--O--CO--CH.sub.3 H Cl Cl H Cl 0622
--CO--CH.sub.2--O--CO--CH.sub.3 H H --CF.sub.3 H H 0623
--CO--CH.sub.2--O--CO--CH.sub.3 H H --OCF.sub.3 H H 0624
--CO--CH.sub.2--O--CO--CH.sub.3 H H --C.sub.2F.sub.5 H H 0625
--CO--CH.sub.2--O--CO--CH.sub.3 H H --C.sub.4H.sub.9-tert H H 0626
--CO--CH.sub.2--O--CO--CH.sub.3 H H --OC.sub.3H.sub.7-i H H 0627
--CO--CH.sub.2--O--CO--CH.sub.3 H H --SO--CH.sub.3 H H 0628
--CO--CH.sub.2--O--CO--CH.sub.3 H H --SO.sub.2--CH.sub.3 H H 0629
--CO--CH.sub.2--O--CO--CH.sub.3 H H --NH--CH.sub.2--CH.sub.3 H H
0630 --CO--CH.sub.2--O--CO--CH.sub.3 H H
--O--CH.sub.2--CH.dbd.CH.sub.2 H H 0631
--CO--CH.sub.2--O--CO--CH.sub.3 H H --O--CH.sub.2--C.dbd.CH H H
0632 --CO--CH.sub.2--O--CO--CH.sub.3 H H
--NH--CH.sub.2--CH.sub.2--NH--CH.sub.3 H H 0633
--CO--CH.sub.2--O--CO--CH.sub.3 H H --SO.sub.2--C.sub.2H.sub.5 H H
0634 --CO--CH.sub.2--O--CO--CH.sub.3 H H --SO.sub.2--CH.sub.3 Cl H
0635 --CO--C.sub.2F.sub.5 H H --CH.sub.2--O--CH.sub.3 H H 0636
--CO--C.sub.2F.sub.5 H H --NH--CO--CH.sub.3 H H 0637
--CO--C.sub.2F.sub.5 H H --CH.sub.2--NH--CO--CH.sub.3 H H 0638
--CO--C.sub.2F.sub.5 H H --CH(CH.sub.3)--NH--CO--CH.sub.3 H H 0639
--CO--C.sub.2F.sub.5 H H --C(CH.sub.3).sub.2--NH--CO--CH.sub.3 H H
0640 --CO--C.sub.2F.sub.5 H H --CH(CH.sub.3)--O--CH.sub.3 H H 0641
--CO--C.sub.2F.sub.5 H H --C(CH.sub.3).sub.2--O--CH.sub.3 H H 0642
--CO--C.sub.2F.sub.5 H H --CH(CH.sub.3)--O--CO--CH.sub.3 H H 0643
--CO--C.sub.2F.sub.5 H H --CH.sub.2--O--CO--CH.sub.3 H H 0644
--CO--C.sub.2F.sub.5 H H --C(CH.sub.3).sub.2--O--CO--CH.sub.3 H H
0645 --CO--C.sub.2F.sub.5 H H --CH.sub.2--CH.sub.2--O--H H H 0646
--CO--C.sub.2F.sub.5 H H --CH.sub.2--CH.sub.2--O--CH.sub.3 H H 0647
--CO--C.sub.2F.sub.5 H H 157 H H 0648 --CO--C.sub.2F.sub.5 H H 158
H H 0649 --CO--C.sub.2F.sub.5 H H 159 H H 0650 --CO--C.sub.2F.sub.5
H H 160 H H 0651 --CO--C.sub.2F.sub.5 H H 161 H H 0652
--CO--C.sub.2F.sub.5 H H 162 H H 0653 --CO--C.sub.2F.sub.5 H H 163
H H 0654 --CO--C.sub.2F.sub.5 H H 164 H H 0655 --CO--C.sub.2F.sub.5
H H 165 H H 0656 --CO--C.sub.2F.sub.5 H H 166 H H 0657
--CO--C.sub.2F.sub.5 H H 167 H H 0658 --CO--C.sub.2F.sub.5 H H H H
H 0659 --CO--C.sub.2F.sub.5 H H CN H H 0660 --CO--C.sub.2F.sub.5 H
H --C(CH.sub.3).sub.2--OH H H 0661 --CO--C.sub.2F.sub.5 H H
--CH.sub.2--OH H H 0662 --CO--C.sub.2F.sub.5 H H --CO--CH.sub.3 H H
0663 --CO--C.sub.2F.sub.5 H H --C(.dbd.NOH)--CH.sub.3 H H 0664
--CO--C.sub.2F.sub.5 H H --CH(OH)--CH.sub.3 H H 0665
--CO--C.sub.2F.sub.5 H H (3) --CO--O--CH.sub.2-- (4) H 0666
--CO--C.sub.2F.sub.5 H H --CH.sub.2--O--CO--CH.sub.3 H H 0667
--CO--C.sub.2F.sub.5 H H --C(.dbd.NO--CH.sub.3)--CH.sub.3 H H 0668
--CO--C.sub.2F.sub.5 H H --CO--O--CH.sub.3 H H 0669
--CO--C.sub.2F.sub.5 H H --NH--CO--C.sub.3H.sub.5-cycl. H H 0670
--CO--C.sub.2F.sub.5 H H --CO--CH.sub.3 Cl H 0671
--CO--C.sub.2F.sub.5 H H --OH H H 0672 --CO--C.sub.2F.sub.5 H H
--OH --OCH.sub.3 H 0673 --CO--C.sub.2F.sub.5 H H --OCH.sub.3 H
--OCH.sub.3 0674 --CO--C.sub.2F.sub.5 H H --SCH.sub.3 H H 0675
--CO--C.sub.2F.sub.5 H H --OCH.sub.3 H H 0676 --CO--C.sub.2F.sub.5
H H --OCH.sub.3 --OCH.sub.3 --OCH.sub.3 0677 --CO--C.sub.2F.sub.5 H
H --OH --OCH.sub.3 --OCH.sub.3 0678 --CO--C.sub.2F.sub.5 H H H
--SCH.sub.3 H 0679 --CO--C.sub.2F.sub.5 H H H --OCH.sub.3 H 0680
--CO--C.sub.2F.sub.5 H H --OCH.sub.3 --OH H 0681
--CO--C.sub.2F.sub.5 H --OCH.sub.3 --CH.sub.3 H H 0682
--CO--C.sub.2F.sub.5 H H --CH.sub.2--CH.sub.3 H H 0683
--CO--C.sub.2F.sub.5 H --OCH.sub.3 --CH(CH.sub.3).sub.2 H H 0684
--CO--C.sub.2F.sub.5 H H --C.sub.3H.sub.7-n H H 0685
--CO--C.sub.2F.sub.5 H H --OCH.sub.2--CH.sub.3 H H 0686
--CO--C.sub.2F.sub.5 H H F H H 0687 --CO--C.sub.2F.sub.5 H H Cl H H
0688 --CO--C.sub.2F.sub.5 H H Br H H 0689 --CO--C.sub.2F.sub.5 H H
Cl Cl H 0690 --CO--C.sub.2F.sub.5 H H OH OH OH 0691
--CO--C.sub.2F.sub.5 H Cl Cl H Cl 0692 --CO--C.sub.2F.sub.5 H H
--CF.sub.3 H H 0693 --CO--C.sub.2F.sub.5 H H --OCF.sub.3 H H 0694
--CO--C.sub.2F.sub.5 H H --C.sub.2F.sub.5 H H 0695
--CO--C.sub.2F.sub.5 H H --C.sub.4H.sub.9-tert H H 0696
--CO--C.sub.2F.sub.5 H H --OC.sub.3H.sub.7-i H H 0697
--CO--C.sub.2F.sub.5 H H --SO--CH.sub.3 H H 0698
--CO--C.sub.2F.sub.5 H H --SO.sub.2--CH.sub.3 H H 0699
--CO--C.sub.2F.sub.5 H H --NH --CH.sub.2--CH.sub.3 H H 0700
--CO--C.sub.2F.sub.5 H H --O--CH.sub.2--CH.dbd.CH.sub.2 H H 0701
--CO--C.sub.2F.sub.5 H H --O--CH.sub.2--C.dbd.CH H H 0702
--CO--C.sub.2F.sub.5 H H --NH--CH.sub.2--CH.sub.2--NH--CH.sub.3 H H
0703 --CO--C.sub.2F.sub.5 H H --SO.sub.2--C.sub.2H.sub.5 H H 0704
--CO--C.sub.2F.sub.5 H H --SO.sub.2--CH.sub.3 Cl H 0705
--CO--CF.sub.3 H H --CH.sub.2--O--CH.sub.3 H H 0706 --CO--CF.sub.3
H H --NH--CO--CH.sub.3 H H 0707 --CO--CF.sub.3 H H
--CH.sub.2--NH--CO--CH.sub.3 H H 0708 --CO--CF.sub.3 H H
--CH(CH.sub.3)--NH--CO--CH.sub.3 H H 0709 --CO--CF.sub.3 H H
--C(CH.sub.3).sub.2--NH--CO--CH.sub.3 H H 0710 --CO--CF.sub.3 H H
--CH(CH.sub.3)--O--CH.sub.3 H H 0711 --CO--CF.sub.3 H H
--C(CH.sub.3).sub.2--O--CH.sub.3 H H 0712 --CO--CF.sub.3 H H
--CH(CH.sub.3)--O--CO--CH.sub.3 H H 0713 --CO--CF.sub.3 H H
--CH.sub.2--O--CO--CH.sub.3 H H 0714 --CO--CF.sub.3 H H
--C(CH.sub.3).sub.2--O--CO--CH.sub.3 H H 0715 --CO--CF.sub.3 H H
--CH.sub.2--CH.sub.2--O--H H H 0716 --CO--CF.sub.3 H H
--CH.sub.2--CH.sub.2--O--CH.sub.3 H H 0717 --CO--CF.sub.3 H H 168 H
H 0718 --CO--CF.sub.3 H H 169 H H 0719 --CO--CF.sub.3 H H 170 H H
0720 --CO--CF.sub.3 H H 171 H H 0721 --CO--CF.sub.3 H H 172 H H
0722 --CO--CF.sub.3 H H 173 H H 0723 --CO--CF.sub.3 H H 174 H H
0724 --CO--CF.sub.3 H H 175 H H 0725 --CO--CF.sub.3 H H 176 H H
0726 --CO--CF.sub.3 H H 177 H H 0727 --CO--CF.sub.3 H H 178 H H
0728 --CO--CF.sub.3 H H 179 H H 0729 --CO--CF.sub.3 H H H H H 0730
--CO--CF.sub.3 H H CN H H 0731 --CO--CF.sub.3 H H
--C(CH.sub.3).sub.2--OH H H 0732 --CO--CF.sub.3 H H --CH.sub.2--OH
H H 0733 --CO--CF.sub.3 H H --CO--CH.sub.3 H H 0734 --CO--CF.sub.3
H H --C(.dbd.NOH)--CH.sub.3 H H 0735 --CO--CF.sub.3 H H
--CH(OH)--CH.sub.3 H H 0736 --CO--CF.sub.3 H H (3)
--CO--O--CH.sub.2-- (4) H 0737 --CO--CF.sub.3 H H
--CH.sub.2--O--CO--CH.sub.3 H H 0738 --CO--CF.sub.3 H H
--C(.dbd.NO--CH.sub.3)--CH.sub.3 H H 0739 --CO--CF.sub.3 H H
--CO--O--CH.sub.3 H H 0740 --CO--CF.sub.3 H H
--NH--CO--C.sub.3H.sub.5-cycl. H H 0741 --CO--CF.sub.3 H H
--CO--CH.sub.3 Cl H 0742 --CO--CF.sub.3 H H --OH H H 0743
--CO--CF.sub.3 H H --OH --OCH.sub.3 H 0744 --CO--CF.sub.3 H H
--OCH.sub.3 H --OCH.sub.3 0745 --CO--CF.sub.3 H H --SCH.sub.3 H H
0746 --CO--CF.sub.3 H H --OCH.sub.3 H H 0747 --CO--CF.sub.3 H H
--OCH.sub.3 --OCH.sub.3 --OCH.sub.3 0748 --CO--CF.sub.3 H H --OH
--OCH.sub.3 --OCH.sub.3 0749 --CO--CF.sub.3 H H H --SCH.sub.3 H
0750 --CO--CF.sub.3 H H H --OCH.sub.3 H 0751 --CO--CF.sub.3 H H
--OCH.sub.3 --OH H 0752 --CO--CF.sub.3 H --OCH.sub.3 --CH.sub.3 H H
0753 --CO--CF.sub.3 H --OCH.sub.3 --CH(CH.sub.3).sub.2 H H 0754
--CO--CF.sub.3 H H --C.sub.3H.sub.7-n H H 0755 --CO--CF.sub.3 H H
--OCH.sub.2--CH.sub.3 H H 0756 --CO--CF.sub.3 H H F H H 0757
--CO--CF.sub.3 H H Cl H H 0758 --CO--CF.sub.3 H H Br H H 0759
--CO--CF.sub.3 H H Cl Cl H 0760 --CO--CF.sub.3 H H OH OH OH 0761
--CO--CF.sub.3 H Cl Cl H Cl 0762 --CO--CF.sub.3 H H --CF.sub.3 H H
0763 --CO--CF.sub.3 H H --OCF.sub.3 H H 0764 --CO--CF.sub.3 H H
--C.sub.2F.sub.5 H H 0765 --CO--CF.sub.3 H H --C.sub.4H.sub.9-tert
H H 0766 --CO--CF.sub.3 H H --OC.sub.3H.sub.7-i H H 0767
--CO--CF.sub.3 H H --SO--CH.sub.3 H H 0768 --CO--CF.sub.3 H H
--SO.sub.2--CH.sub.3 H H 0769 --CO--CF.sub.3 H H
--NH--CH.sub.2--CH.sub.3 H H 0770 --CO--CF.sub.3 H H
--O--CH.sub.2--CH.dbd.CH.sub.2 H H 0771 --CO--CF.sub.3 H H
--O--CH.sub.2--C.dbd.CH H H 0772 --CO--CF.sub.3 H H
--NH--CH.sub.2--CH.sub.2--NH--CH.sub.3 H H 0773 --CO--CF.sub.3 H H
--SO.sub.2--C.sub.2H.sub.5 H H 0774 --CO--CF.sub.3 H H
--SO.sub.2--CH.sub.3 Cl H 0775 --(CH.sub.2).sub.4-- H
--CH.sub.2--O--CH.sub.3 H H 0776 --(CH.sub.2).sub.4-- H
--NH--CO--CH.sub.3 H H 0777 --(CH.sub.2).sub.4-- H
--CH.sub.2--NH--CO--CH.sub.3 H H 0778 --(CH.sub.2).sub.4-- H
--CH(CH.sub.3)--NH--CO--CH.sub.3 H H 0779 --(CH.sub.2).sub.4-- H
--C(CH.sub.3).sub.2--NH--CO--CH.sub.3 H H 0780 --(CH.sub.2).sub.4--
H --CH(CH.sub.3)--O--CH.sub.3 H H 0781 --(CH.sub.2).sub.4-- H
--C(CH.sub.3).sub.2--O--CH.sub.3 H H 0782 --(CH.sub.2).sub.4-- H
--CH(CH.sub.3)--O--CO--CH.sub.3 H H 0783 --(CH.sub.2).sub.4-- H
--CH.sub.2--O--CO--CH.sub.3 H H 0784 --(CH.sub.2).sub.4-- H
--C(CH.sub.3).sub.2--O--CO--CH.sub.3 H H 0785 --(CH.sub.2).sub.4--
H --CH.sub.2--CH.sub.2--O--H H H 0786 --(CH.sub.2).sub.4-- H
--CH.sub.2--CH.sub.2--O--CH.sub.3 H H 0787 --(CH.sub.2).sub.4-- H
180 H H 0788 --(CH.sub.2).sub.4-- H 181 H H 0789
--(CH.sub.2).sub.4-- H 182 H H 0790 --(CH.sub.2).sub.4-- H 183 H H
0791 --(CH.sub.2).sub.4-- H 184 H H 0792 --(CH.sub.2).sub.4-- H 185
H H 0793 --(CH.sub.2).sub.4-- H 186 H H 0794 --(CH.sub.2).sub.4-- H
187 H H 0795 --(CH.sub.2).sub.4-- H 188 H H 0796
--(CH.sub.2).sub.4-- H 189 H H 0797 --(CH.sub.2).sub.4-- H 190 H H
0798 --(CH.sub.2).sub.4-- H 191 H H 0799 --(CH.sub.2).sub.4-- H H H
H 0800 --(CH.sub.2).sub.4-- H CN H H 0801 --(CH.sub.2).sub.4-- H
--C(CH.sub.3).sub.2--OH H H 0802 --(CH.sub.2).sub.4-- H
--CH.sub.2--OH H H 0803 --(CH.sub.2).sub.4-- H --CO--CH.sub.3 H H
0804 --(CH.sub.2).sub.4-- H --C(.dbd.NOH)--CH.sub.3 H H 0805
--(CH.sub.2).sub.4-- H --CH(OH)--CH.sub.3 H H 0806
--(CH.sub.2).sub.4-- H (3) --CO--O--CH.sub.2-- (4) H 0807
--(CH.sub.2).sub.4-- H --CH.sub.2--O--CO--CH.sub.3 H H 0808
--(CH.sub.2).sub.4-- H --C(.dbd.NO--CH.sub.3)--CH.sub.3 H H 0809
--(CH.sub.2).sub.4-- H --CO--O--CH.sub.3 H H 0810
--(CH.sub.2).sub.4-- H --NH--CO--C.sub.3H.sub.5-cycl. H H 0811
--(CH.sub.2).sub.4-- H --CO--CH.sub.3 Cl H 0812
--(CH.sub.2).sub.4-- H --OH H H 0813 --(CH.sub.2).sub.4-- H --OH
--OCH.sub.3 H 0814 --(CH.sub.2).sub.4-- H --OCH.sub.3 H --OCH.sub.3
0815 --(CH.sub.2).sub.4-- H --SCH.sub.3 H H 0816
--(CH.sub.2).sub.4-- H --OCH.sub.3 H H 0817 --(CH.sub.2).sub.4-- H
--OCH.sub.3 --OCH.sub.3 --OCH.sub.3 0818 --(CH.sub.2).sub.4-- H
--OH --OCH.sub.3 --OCH.sub.3 0819 --(CH.sub.2).sub.4-- H H
--SCH.sub.3 H 0820 --(CH.sub.2).sub.4-- H H --OCH.sub.3 H 0821
--(CH.sub.2).sub.4-- H --OCH.sub.3 --OH H 0822 --(CH.sub.2).sub.4--
--OCH.sub.3 --CH.sub.3 H H 0823 --(CH.sub.2).sub.4-- H
--CH.sub.2--CH.sub.3 H H 0824 --(CH.sub.2).sub.4-- --OCH.sub.3
--CH(CH.sub.3).sub.2 H H 0825 --(CH.sub.2).sub.4-- H
--C.sub.3H.sub.7-n H H 0826 --(CH.sub.2).sub.4-- H
--OCH.sub.2--CH.sub.3 H H 0827 --(CH.sub.2).sub.4-- H F H H 0828
--(CH.sub.2).sub.4-- H Cl H H 0829 --(CH.sub.2).sub.4-- H Br H H
0830 --(CH.sub.2).sub.4-- H Cl Cl H 0831 --(CH.sub.2).sub.4-- H OH
OH OH 0832 --(CH.sub.2).sub.4-- Cl Cl H Cl 0833
--(CH.sub.2).sub.4-- H --CF.sub.3 H H 0834 --(CH.sub.2).sub.4-- H
--OCF.sub.3 H H 0835 --(CH.sub.2).sub.4-- H --C.sub.2F.sub.5 H H
0836 --(CH.sub.2).sub.4-- H --C.sub.4H.sub.9-tert H H 0837
--(CH.sub.2).sub.4-- H --OC.sub.3H.sub.7-i H H 0838
--(CH.sub.2).sub.4-- H --SO--CH.sub.3 H H 0839 --(CH.sub.2).sub.4--
H --SO.sub.2--CH.sub.3 H H 0840 --(CH.sub.2).sub.4-- H
--NH--CH.sub.2--CH.sub.3 H H 0841 --(CH.sub.2).sub.4-- H
--O--CH.sub.2--CH.dbd.CH.sub.2 H H 0842 --(CH.sub.2).sub.4-- H
--O--CH.sub.2--C.dbd.CH H H 0843 --(CH.sub.2).sub.4-- H
--NH--CH.sub.2--CH.sub.2--NH--CH.sub.3 H H 0844
--(CH.sub.2).sub.4-- H --SO.sub.2--C.sub.2H.sub.5 H H 0845
--(CH.sub.2).sub.4-- H --SO.sub.2--CH.sub.3 Cl H 0846
--N.dbd.C(CH.sub.3)--N(CH.sub.3).sub.2 H --CH.sub.2--O--CH.sub.3 H
H 0847 --N.dbd.C(CH.sub.3)--N(CH.sub.3).sub.2 H --NH--CO--CH.sub.3
H H 0848 --N.dbd.C(CH.sub.3)--N(CH.sub.3).sub.2 H
--CH.sub.2--NH--CO--CH.- sub.3 H H 0849
--N.dbd.C(CH.sub.3)--N(CH.sub.3).sub.2 H
--CH(CH.sub.3)--NH--CO--CH.sub.3 H H 0850 --N.dbd.C(CH.sub.3)--N(C-
H.sub.3).sub.2 H --C(CH.sub.3).sub.2--NH--CO--CH.sub.3 H H 0851
--N.dbd.C(CH.sub.3)--N(CH.sub.3).sub.2 H
--CH(CH.sub.3)--O--CH.sub.3 H H 0852
--N.dbd.C(CH.sub.3)--N(CH.sub.3).sub.2 H
--C(CH.sub.3).sub.2--O--CH.sub.3 H H 0853 --N.dbd.C(CH.sub.3)--N(C-
H.sub.3).sub.2 H --CH.sub.2--O--CO--CH.sub.3 H H 0854
--N.dbd.C(CH.sub.3)--N(CH.sub.3).sub.2 H
--C(CH.sub.3).sub.2--O--CO--CH.s- ub.3 H H 0855
--N.dbd.C(CH.sub.3)--N(CH.sub.3).sub.2 H --CH.sub.2--CH.sub.2--O--H
H H 0856 --N.dbd.C(CH.sub.3)--N(CH.sub.- 3).sub.2 H
--CH.sub.2--CH.sub.2--O--CH.sub.3 H H 0857
--N.dbd.C(CH.sub.3)--N(CH.sub.3).sub.2 H 192 H H 0858
--N.dbd.C(CH.sub.3)--N(CH.sub.3).sub.2 H 193 H H 0859
--N.dbd.C(CH.sub.3)--N(CH.sub.3).sub.2 H 194 H H 0860
--N.dbd.C(CH.sub.3)--N(CH.sub.3).sub.2 H 195 H H 0861
--N.dbd.C(CH.sub.3)--N(CH.sub.3).sub.2 H 196 H H 0862
--N.dbd.C(CH.sub.3)--N(CH.sub.3).sub.2 H 197 H H 0863
--N.dbd.C(CH.sub.3)--N(CH.sub.3).sub.2 H 198 H H 0864
--N.dbd.C(CH.sub.3)--N(CH.sub.3).sub.2 H 199 H H 0865
--N.dbd.C(CH.sub.3)--N(CH.sub.3).sub.2 H 200 H H 0866
--N.dbd.C(CH.sub.3)--N(CH.sub.3).sub.2 H 201 H H 0867
--N.dbd.C(CH.sub.3)--N(CH.sub.3).sub.2 H 202 H H 0868
--N.dbd.C(CH.sub.3)--N(CH.sub.3).sub.2 H 203 H H 0869
--N.dbd.C(CH.sub.3)--N(CH.sub.3).sub.2 H H H H 0870
--N.dbd.C(CH.sub.3)--N(CH.sub.3).sub.2 H CN H H 0871
--N.dbd.C(CH.sub.3)--N(CH.sub.3).sub.2 H --C(CH.sub.3).sub.2--OH H
H 0872 --N.dbd.C(CH.sub.3)--N(CH.sub.3).sub.2 H --CH.sub.2--OH H H
0873 --N.dbd.C(CH.sub.3)--N(CH.sub.3).sub.2 H --CO--CH.sub.3 H H
0874 --N.dbd.C(CH.sub.3)--N(CH.sub.3).sub.2 H
--C(.dbd.NOH)--CH.sub.3 H H 0875
--N.dbd.C(CH.sub.3)--N(CH.sub.3).sub.2 H --CH(OH)--CH.sub.3 H H
0876 --N.dbd.C(CH.sub.3)--N(CH.sub.3).sub.2 H (3)
--CO--O--CH.sub.2-- (4) H 0877 --N.dbd.C(CH.sub.3)--N(CH.sub.3).s-
ub.2 H --CH.sub.2--O--CO--CH.sub.3 H H 0878
--N.dbd.C(CH.sub.3)--N(- CH.sub.3).sub.2 H
--C(.dbd.NO--CH.sub.3)--CH.sub.3 H H 0879
--N.dbd.C(CH.sub.3)--N(CH.sub.3).sub.2 H --CO--O--CH.sub.3 H H 0880
--N.dbd.C(CH.sub.3)--N(CH.sub.3).sub.2 H
--NH--CO--C.sub.3H.sub.5-cy- cl. H H 0881
--N.dbd.C(CH.sub.3)--N(CH.sub.3).sub.2 H --CO--CH.sub.3 Cl H 0882
--N.dbd.C(CH.sub.3)--N(CH.sub.3).sub.2 H --OH H H 0883
--N.dbd.C(CH.sub.3)--N(CH.sub.3).sub.2 H --OH --OCH.sub.3 H 0884
--N.dbd.C(CH.sub.3)--N(CH.sub.3).sub.2 H --OCH.sub.3 H --OCH.sub.3
0885 --N.dbd.C(CH.sub.3)--N(CH.sub.3).su- b.2 H --SCH.sub.3 H H
0886 --N.dbd.C(CH.sub.3)--N(CH.sub.3).sub.2 H --OCH.sub.3 H H 0887
--N.dbd.C(CH.sub.3)--N(CH.sub.3).sub.2 H OCH.sub.3 --OCH.sub.3
--OCH.sub.3 0888 --N.dbd.C(CH.sub.3)--N(CH.s- ub.3).sub.2 H --OH
--OCH.sub.3 --OCH.sub.3 0889 --N.dbd.C(CH.sub.3)--N(CH.sub.3).sub.2
H H --SCH.sub.3 H 0890 --N.dbd.C(CH.sub.3)--N(CH.sub.3).sub.2 H H
--SCH.sub.3 H 0891 --N.dbd.C(CH.sub.3)--N(CH.sub.3).sub.2 H
--OCH.sub.3 --OH H 0892 --N.dbd.C(CH.sub.3)--N(CH.sub.3).sub.2
--OCH.sub.3 --CH.sub.3 H H 0893
--N.dbd.C(CH.sub.3)--N(CH.sub.3).sub.2 H --CH.sub.2--CH.sub.3 H H
0894 --N.dbd.C(CH.sub.3)--N(CH.sub.3).sub.2 --OCH.sub.3
--CH(CH.sub.3).sub.2 H H 0895 --N.dbd.C(CH.sub.3)--N(CH.sub.3).sub-
.2 H --C.sub.3H.sub.7-n H H 0896
--N.dbd.C(CH.sub.3)--N(CH.sub.3).s- ub.2 H --OCH.sub.2--CH.sub.3 H
H 0897 --N.dbd.C(CH.sub.3)--N(CH.sub- .3).sub.2 H F H H 0898
--N.dbd.C(CH.sub.3)--N(CH.sub.3).sub.2 H Cl H H 0899
--N.dbd.C(CH.sub.3)--N(CH.sub.3).sub.2 H Br H H 0900
--N.dbd.C(CH.sub.3)--N(CH.sub.3).sub.2 H Cl Cl H 0901
--N.dbd.C(CH.sub.3)--N(CH.sub.3).sub.2 H OH OH OH 0902
--N.dbd.C(CH.sub.3)--N(CH.sub.3).sub.2 Cl Cl H Cl 0903
--N.dbd.C(CH.sub.3)--N(CH.sub.3).sub.2 H --CF.sub.3 H H 0904
--N.dbd.C(CH.sub.3)--N(CH.sub.3).sub.2 H --OCF.sub.3 H H 0905
--N.dbd.C(CH.sub.3)--N(CH.sub.3).sub.2 H --C.sub.2F.sub.5 H H 0906
--N.dbd.C(CH.sub.3)--N(CH.sub.3).sub.2 H --C.sub.4H.sub.9-tert H H
0907 --N.dbd.C(CH.sub.3)--N(CH.sub.3).sub.2 H --OC.sub.3H.sub.7-i H
H 0908 --N.dbd.C(CH.sub.3)--N(CH.sub.3).sub.2 H --SO--CH.sub.3 H H
0909 --N.dbd.C(CH.sub.3)--N(CH.sub.3).sub.2 H --SO.sub.2--CH.sub.3
H H 0910 --N.dbd.C(CH.sub.3)--N(CH.sub.3).sub.2 H
--NH--CH.sub.2--CH.sub.3 H H 0911 --N.dbd.C(CH.sub.3)--N(CH.sub.3)-
.sub.2 H --O--CH.sub.2--CH.dbd.CH.sub.2 H H 0912
--N.dbd.C(CH.sub.3)--N(CH.sub.3).sub.2 H --O--CH.sub.2--C.dbd.CH H
H 0913 --N.dbd.C(CH.sub.3)--N(CH.sub.3).sub.2 H
--NH--CH.sub.2--CH.sub.2-- -NH--CH.sub.3 H H 0914
--N.dbd.C(CH.sub.3)--N(CH.sub.3).sub.2 H --SO.sub.2--C.sub.2H.sub.5
H H 0915 --N.dbd.C(CH.sub.3)--N(CH.sub.- 3).sub.2 H
--SO.sub.2--CH.sub.3 Cl H 0916 --N.dbd.CH--N(CH.sub.3).s- ub.2 H
--CH.sub.2--O--CH.sub.3 H H 0917 --N.dbd.CH--N(CH.sub.3).sub- .2 H
--NH--CO--CH.sub.3 H H 0918 --N.dbd.CH--N(CH.sub.3).sub.2 H
--CH.sub.2--NH--CO--CH.sub.3 H H 0919 --N.dbd.CH--N(CH.sub.3).sub.-
2 H --CH(CH.sub.3)--NH--CO--CH.sub.3 H H 0920
--N.dbd.CH--N(CH.sub.3).sub.2 H
--C(CH.sub.3).sub.2--NH--CO--CH.sub.3 H H 0921
--N.dbd.CH--N(CH.sub.3).sub.2 H --CH(CH.sub.3)--O--CH.sub.3 H H
0922 --N.dbd.CH--N(CH.sub.3).sub.2 H --C(CH.sub.3).sub.2--O--CH.-
sub.3 H H 0923 --N.dbd.CH--N(CH.sub.3).sub.2 H
--CH(CH.sub.3)--O--CO--CH.sub.3 H H 0924 --N.dbd.CH--N(CH.sub.3).s-
ub.2 H --CH.sub.2--O--CO--CH.sub.3 H H 0925
--N.dbd.CH--N(CH.sub.3)- .sub.2 H
--C(CH.sub.3).sub.2--O--CO--CH.sub.3 H H 0926
--N.dbd.CH--N(CH.sub.3).sub.2 H --CH.sub.2--CH.sub.2--O--H H H 0927
--N.dbd.CH--N(CH.sub.3).sub.2 H --CH.sub.2--CH.sub.2--O--CH.sub.3 H
H 0928 --N.dbd.CH--N(CH.sub.3).sub.2 H 204 H H 0929
--N.dbd.CH--N(CH.sub.3).sub.2 H 205 H H 0930
--N.dbd.CH--N(CH.sub.3).sub.2 H 206 H H 0931
--N.dbd.CH--N(CH.sub.3).sub.2 H 207 H H 0932
--N.dbd.CH--N(CH.sub.3).sub.2 H 208 H H 0933
--N.dbd.CH--N(CH.sub.3).sub.2 H 209 H H 0934
--N.dbd.CH--N(CH.sub.3).sub.2 H 210 H H 0935
--N.dbd.CH--N(CH.sub.3).sub.2 H 211 H H 0936
--N.dbd.CH--N(CH.sub.3).sub.2 H 212 H H 0937
--N.dbd.CH--N(CH.sub.3).sub.2 H 213 H H 0938
--N.dbd.CH--N(CH.sub.3).sub.2 H 214 H H 0939
--N.dbd.CH--N(CH.sub.3).sub.2 H 215 H H 0940
--N.dbd.CH--N(CH.sub.3).sub.2 H H H H 0941 --N.dbd.CH--N(CH.sub.3)-
.sub.2 H CN H H 0942 --N.dbd.CH--N(CH.sub.3).sub.2 H
--C(CH.sub.3).sub.2--OH H H 0943 --N.dbd.CH--N(CH.sub.3).sub.2 H
--CH.sub.2--OH H H 0944 --N.dbd.CH--N(CH.sub.3).sub.2 H
--CO--CH.sub.3 H H 0945 --N.dbd.CH--N(CH.sub.3).sub.2 H
--C(.dbd.NOH)--CH.sub.3 H H 0946 --N.dbd.CH--N(CH.sub.3).sub.2 H
--CH(OH)--CH.sub.3 H H 0947 --N.dbd.CH--N(CH.sub.3).sub.2 H (3)
--CO--O--CH.sub.2-- (4) H 0948 --N.dbd.CH--N(CH.sub.3).sub.2 H
--CH.sub.2--O--CO--CH.sub.3 H H 0949 --N.dbd.CH--N(CH.sub.3).sub.2
H --C(.dbd.NO--CH.sub.3)--CH.sub.3 H H 0950
--N.dbd.CH--N(CH.sub.3).sub.2 H --CO--O--CH.sub.3 H H 0951
--N.dbd.CH--N(CH.sub.3).sub.2 H --NH--CO--C.sub.3H.sub.5-cycl. H H
0952 --N.dbd.CH--N(CH.sub.3).sub.2 H --CO--CH.sub.3 Cl H 0953
--N.dbd.CH--N(CH.sub.3).sub.2 H --OH --OCH.sub.3 H 0954
--N.dbd.CH--N(CH.sub.3).sub.2 H --OCH.sub.3 H --OCH.sub.3 0955
--N.dbd.CH--N(CH.sub.3).sub.2 H --SCH.sub.3 H H 0956
--N.dbd.CH--N(CH.sub.3).sub.2 H --OCH.sub.3 H H 0957
--N.dbd.CH--N(CH.sub.3).sub.2 H --OCH.sub.3 --OCH.sub.3 --OCH.sub.3
0958 --N.dbd.CH--N(CH.sub.3).sub.2 H --OH --OCH.sub.3 --OCH.sub.3
0959 --N.dbd.CH--N(CH.sub.3).sub.2 H H --SCH.sub.3 H 0960
--N.dbd.CH--N(CH.sub.3).sub.2 H H --OCH.sub.3 H 0961
--N.dbd.CH--N(CH.sub.3).sub.2 H --OCH.sub.3 --OH H 0962
--N.dbd.CH--N(CH.sub.3).sub.2 --OCH.sub.3 --CH.sub.3 H H 0963
--N.dbd.CH--N(CH.sub.3).sub.2 H --CH.sub.2--CH.sub.3 H H 0964
--N.dbd.CH--N(CH.sub.3).sub.2 --OCH.sub.3 --CH(CH.sub.3).sub.2 H H
0965 --N.dbd.CH--N(CH.sub.3).sub.2 H --C.sub.3H.sub.7-n H H 0966
--N.dbd.CH--N(CH.sub.3).sub.2 H --OCH.sub.2--CH.sub.3 H H 0967
--N.dbd.CH--N(CH.sub.3).sub.2 H F H H 0968 --N.dbd.CH--N(CH.sub.3)-
.sub.2 H Cl H H 0969 --N.dbd.CH--N(CH.sub.3).sub.2 H Br H H 0970
--N.dbd.CH--N(CH.sub.3).sub.2 H Cl Cl H 0971
--N.dbd.CH--N(CH.sub.3).sub.2 H OH OH OH 0972
--N.dbd.CH--N(CH.sub.3).sub.2 Cl Cl H Cl 0973
--N.dbd.CH--N(CH.sub.3).sub.2 H --CF.sub.3 H H 0974
--N.dbd.CH--N(CH.sub.3).sub.2 H --OCF.sub.3 H H 0975
--N.dbd.CH--N(CH.sub.3).sub.2 H --C.sub.2F.sub.5 H H 0976
--N.dbd.CH--N(CH.sub.3).sub.2 H --C.sub.4H.sub.9-tert H H 0977
--N.dbd.CH--N(CH.sub.3).sub.2 H --OC.sub.3H.sub.7-i H H 0978
--N.dbd.CH--N(CH.sub.3).sub.2 H --SO--CH.sub.3 H H 0979
--N.dbd.CH--N(CH.sub.3).sub.2 H --SO.sub.2--CH.sub.3 H H 0980
--N.dbd.CH--N(CH.sub.3).sub.2 H --NH--CH.sub.2--CH.sub.3 H H 0981
--N.dbd.CH--N(CH.sub.3).sub.2 H --O--CH.sub.2--CH.dbd.CH.sub.2 H H
0982 --N.dbd.CH--N(CH.sub.3).sub.2 H --O--CH.sub.2--C.dbd.CH H H
0983 --N.dbd.CH--N(CH.sub.3).sub.2 H
--NH--CH.sub.2--CH.sub.2--NH--CH.sub- .3 H H 0984
--N.dbd.CH--N(CH.sub.3).sub.2 H --SO.sub.2--C.sub.2H.su- b.5 H H
0985 --N.dbd.CH--N(CH.sub.3).sub.2 H --SO.sub.2--CH.sub.3 Cl H 0986
H H --OH H --OCH.sub.3 H 0987 H H --OCH.sub.3 --CH.sub.3 H H 0988 H
H H --SO--CH.sub.3 H H 0989 --CO--C.sub.3H.sub.5-cycl H H
--CH.sub.2--O--CH.sub.3 H H 0990 --CO--C.sub.3H.sub.5-cycl H H
--NH--CO--CH.sub.3 H H 0991 --CO--C.sub.3H.sub.5-cycl H H
--CH.sub.2--NH--CO--CH.sub.3 H H 0992 --CO--C.sub.3H.sub.5-cycl H H
--CH(CH.sub.3)--NH--CO--CH.sub.3 H H 0993 --CO--C.sub.3H.sub.5-cycl
H H --C(CH.sub.3).sub.2--NH--CO--CH.s- ub.3 H H 0994
--CO--C.sub.3H.sub.5-cycl H H --CH(CH.sub.3)--O--CH.s- ub.3 H H
0995 --CO--C.sub.3H.sub.5-cycl H H --C(CH.sub.3).sub.2--O--
-CH.sub.3 H H 0996 --CO--C.sub.3H.sub.5-cycl H H
--CH(CH.sub.3)--O--CO--CH.sub.3 H H 0997 --CO--C.sub.3H.sub.5-cycl
H H --CH.sub.2--O--CO--CH.sub.3 H H 0998 --CO--C.sub.3H.sub.5-cycl
H H --C(CH.sub.3).sub.2--O--CO--CH.sub.3 H H 0999
--CO--C.sub.3H.sub.5-cycl H H --CH.sub.2--CH.sub.2--O--H H H 1000
--CO--C.sub.3H.sub.5-cycl H H --CH.sub.2--CH.sub.2--O--CH.sub.3 H H
1001 --CO--C.sub.3H.sub.5-cycl H H 216 H H 1002
--CO--C.sub.3H.sub.5-cycl H H 217 H H 1003
--CO--C.sub.3H.sub.5-cycl H H 218 H H 1004
--CO--C.sub.3H.sub.5-cycl H H 219 H H 1005
--CO--C.sub.3H.sub.5-cycl H H 220 H H 1006
--CO--C.sub.3H.sub.5-cycl H H 221 H H 1007
--CO--C.sub.3H.sub.5-cycl H H 222 H H 1008
--CO--C.sub.3H.sub.5-cycl H H 223 H H 1009
--CO--C.sub.3H.sub.5-cycl H H 224 H H 1010
--CO--C.sub.3H.sub.5-cycl H H 225 H H 1011
--CO--C.sub.3H.sub.5-cycl H H 226 H H 1012
--CO--C.sub.3H.sub.5-cycl H H 227 H H 1013
--CO--C.sub.3H.sub.5-cycl H H H H H 1014 --CO--C.sub.3H.sub.5-cycl
H H CN H H 1015 --CO--C.sub.3H.sub.5-cycl H H
--C(CH.sub.3).sub.2--OH H H 1016 --CO--C.sub.3H.sub.5-cycl H H
--CH.sub.2--OH H H 1017 --CO--C.sub.3H.sub.5-cycl H H
--CO--CH.sub.3 H H 1018 --CO--C.sub.3H.sub.5-cycl H H
--C(.dbd.NOH)--CH.sub.3 H H 1019 --CO--C.sub.3H.sub.5-cycl H H
--CH(OH)--CH.sub.3 H H 1020 --CO--C.sub.3H.sub.5-cycl H H (3)
--CO--O--CH.sub.2-- (4) H 1021 --CO--C.sub.3H.sub.5-cycl H H
--CH.sub.2--O--CO--CH.sub.3 H H 1022 --CO--C.sub.3H.sub.5-cycl H H
--C(.dbd.NO--CH.sub.3)--CH.sub.3 H H 1023 --CO--C.sub.3H.sub.5-cyc-
l H H --CO--O--CH.sub.3 H H 1024 --CO--C.sub.3H.sub.5-cycl H H
--NH--CO--C.sub.3H.sub.5-cycl. H H 1025 --CO--C.sub.3H.sub.5-cycl H
H --CO--CH.sub.3 Cl H 1026 --CO--C.sub.3H.sub.5-cycl H H --OH H H
1027 --CO--C.sub.3H.sub.5-cycl H H --OH --OCH.sub.3 H 1028
--CO--C.sub.3H.sub.5-cycl H H --OCH.sub.3 H --OCH.sub.3 1029
--CO--C.sub.3H.sub.5-cycl H H --SCH.sub.3 H H 1030
--CO--C.sub.3H.sub.5-cycl H H --OCH.sub.3 H H 1031
--CO--C.sub.3H.sub.5-cycl H H --OCH.sub.3 --OCH.sub.3 --OCH.sub.3
1032 --CO--C.sub.3H.sub.5-cycl H H --OH --OCH.sub.3 --OCH.sub.3
1033 --CO--C.sub.3H.sub.5-cycl H H H --SCH.sub.3 H 1034
--CO--C.sub.3H.sub.5-cycl H H H --OCH.sub.3 H 1035
--CO--C.sub.3H.sub.5-cycl H H --OCH.sub.3 --OH H 1036
--CO--C.sub.3H.sub.5-cycl H --OCH.sub.3 --CH.sub.3 H H 1037
--CO--C.sub.3H.sub.5-cycl H H --CH.sub.2--CH.sub.3 H H 1038
--CO--C.sub.3H.sub.5-cycl H --OCH.sub.3 --CH(CH.sub.3).sub.2 H H
1039 --CO--C.sub.3H.sub.5-cycl H H --C.sub.3H.sub.7-n H H 1040
--CO--C.sub.3H.sub.5-cycl H H --OCH.sub.2--CH.sub.3 H H 1041
--CO--C.sub.3H.sub.5-cycl H H F H H 1042 --CO--C.sub.3H.sub.5-cycl
H H Cl H H 1043 --CO--C.sub.3H.sub.5-cycl H H Br H H 1044
--CO--C.sub.3H.sub.5-cycl H H Cl Cl H 1045 --CO--C.sub.3H.sub.5-cy-
cl H H OH OH OH 1046 --CO--C.sub.3H.sub.5-cycl H Cl Cl H Cl 1047
--CO--C.sub.3H.sub.5-cycl H H --CF.sub.3 H H 1048
--CO--C.sub.3H.sub.5-cycl H H --OCF.sub.3 H H 1049
--CO--C.sub.3H.sub.5-cycl H H --C.sub.2F.sub.5 H H 1050
--CO--C.sub.3H.sub.5-cycl H H --C.sub.4H.sub.9-tert H H 1051
--CO--C.sub.3H.sub.5-cycl H H --OC.sub.3H.sub.7-i H H 1052
--CO--C.sub.3H.sub.5-cycl H H --SO--CH.sub.3 H H 1053
--CO--C.sub.3H.sub.5-cycl H H --NH--CH.sub.2--CH.sub.3 H H 1054
--CO--C.sub.3H.sub.5-cycl H H --O--CH.sub.2--CH.dbd.CH.sub.2 H H
1055 --CO--C.sub.3H.sub.5-cycl H H --O--CH.sub.2--C.dbd.CH H H 1056
--CO--C.sub.3H.sub.5-cycl H H
--NH--CH.sub.2--CH.sub.2--NH--CH.sub.3 H H 1057
--CO--C.sub.3H.sub.5-cycl H H --SO.sub.2--C.sub.2H.sub.5 H H 1058
--CO--C.sub.3H.sub.5-cycl H H --SO.sub.2--CH.sub.3 Cl H 1059
--CO--C(CH.sub.3).sub.2--CH.sub.2--Cl H H --CH.sub.2--O--CH.sub.3 H
H 1060 --CO--C(CH.sub.3).sub.2--CH.sub.2- --Cl H H
--NH--CO--CH.sub.3 H H 1061 --CO--C(CH.sub.3).sub.2--CH.su- b.2--Cl
H H --CH.sub.2--NH--CO--CH.sub.3 H H 1062
--CO--C(CH.sub.3).sub.2--CH.sub.2--Cl H H
--CH(CH.sub.3)--NH--CO--CH.sub.- 3 H H 1063
--CO--C(CH.sub.3).sub.2--CH.sub.2--Cl H H
--C(CH.sub.3).sub.2--NH--CO--CH.sub.3 H H 1064
--CO--C(CH.sub.3).sub.2--CH.sub.2--Cl H H
--CH(CH.sub.3)--O--CH.sub.3 H H 1065
--CO--C(CH.sub.3).sub.2--CH.sub.2--Cl H H
--C(CH.sub.3).sub.2--O--CH.sub.3 H H 1066 --CO--C(CH.sub.3).sub.2--
-CH.sub.2--Cl H H --CH(CH.sub.3)--O--CO--CH.sub.3 H H 1067
--CO--C(CH.sub.3).sub.2--CH.sub.2--Cl H H
--CH.sub.2--O--CO--CH.sub.3 H H 1068
--CO--C(CH.sub.3).sub.2--CH.sub.2--Cl H H
--C(CH.sub.3).sub.2--O--CO--CH.sub.3 H H 1069
--CO--C(CH.sub.3).sub.2--CH.sub.2--Cl H H
--CH.sub.2--CH.sub.2--O--H H H 1070
--CO--C(CH.sub.3).sub.2--CH.sub.2--Cl H H
--CH.sub.2--CH.sub.2--O--CH.sub.3 H H 1071
--CO--C(CH.sub.3).sub.2--CH.sub.2--Cl H H 228 H H 1072
--CO--C(CH.sub.3).sub.2--CH.sub.2--Cl H H 229 H H 1073
--CO--C(CH.sub.3).sub.2--CH.sub.2--Cl H H 230 H H 1074
--CO--C(CH.sub.3).sub.2--CH.sub.2--Cl H H 231 H H 1075
--CO--C(CH.sub.3).sub.2--CH.sub.2--Cl H H 232 H H 1076
--CO--C(CH.sub.3).sub.2--CH.sub.2--Cl H H 233 H H 1077
--CO--C(CH.sub.3).sub.2--CH.sub.2--Cl H H 234 H H 1078
--CO--C(CH.sub.3).sub.2--CH.sub.2--Cl H H 235 H H 1079
--CO--C(CH.sub.3).sub.2--CH.sub.2--Cl H H 236 H H 1080
--CO--C(CH.sub.3).sub.2--CH.sub.2--Cl H H 237 H H 1081
--CO--C(CH.sub.3).sub.2--CH.sub.2--Cl H H 238 H H 1082
--CO--C(CH.sub.3).sub.2--CH.sub.2--Cl H H 239 H H 1083
--CO--C(CH.sub.3).sub.2--CH.sub.2--Cl H H H H H 1084
--CO--C(CH.sub.3).sub.2--CH.sub.2--Cl H H CN H H 1085
--CO--C(CH.sub.3).sub.2--CH.sub.2--Cl H H --C(CH.sub.3).sub.2--OH H
H 1086 --CO--C(CH.sub.3).sub.2--CH.sub.2--Cl H H --CH.sub.2--OH H H
1087 --CO--C(CH.sub.3).sub.2--CH.sub.2--Cl H H --CO--CH.sub.3 H H
1088 --CO--C(CH.sub.3).sub.2--CH.sub.2--Cl H H
--C(.dbd.NOH)--CH.sub.3 H H 1089
--CO--C(CH.sub.3).sub.2--CH.sub.2--Cl H H --CH(OH)--CH.sub.3 H H
1090 --CO--C(CH.sub.3).sub.2--CH.sub.2--Cl H H (3)
--CO--O--CH.sub.2-- (4) H 1091 --CO--C(CH.sub.3).sub.2--C-
H.sub.2--Cl H H --CH.sub.2--O--CO--CH.sub.3 H H 1092
--CO--C(CH.sub.3).sub.2--CH.sub.2--Cl H H
--C(.dbd.NO--CH.sub.3)--CH.sub.- 3 H H 1093
--CO--C(CH.sub.3).sub.2--CH.sub.2--Cl H H --CO--O--CH.sub.3 H H
1094 --CO--C(CH.sub.3).sub.2--CH.sub.2--Cl H H
--NH--CO--C.sub.3H.sub.5-cycl. H H 1095 --CO--C(CH.sub.3).sub.2--
-CH.sub.2--Cl H H --CO--CH.sub.3 Cl H 1096
--CO--C(CH.sub.3).sub.2-- -CH.sub.2--Cl H H --OH H H 1097
--CO--C(CH.sub.3).sub.2--CH.sub.2--- Cl H H --OH --OCH.sub.3 H 1098
--CO--C(CH.sub.3).sub.2--CH.sub.2--C- l H H --OCH.sub.3 H
--OCH.sub.3 1099 --CO--C(CH.sub.3).sub.2--CH.su- b.2--Cl H H
--SCH.sub.3 H H 1100 --CO--C(CH.sub.3).sub.2--CH.sub.2-- -Cl H H
--OCH.sub.3 H H 1101 --CO--C(CH.sub.3).sub.2--CH.sub.2--Cl H H
--OCH.sub.3 --OCH.sub.3 --OCH.sub.3 1102
--CO--C(CH.sub.3).sub.2--CH.sub.2--Cl H H --OH --OCH.sub.3
--OCH.sub.3 1103 --CO--C(CH.sub.3).sub.2--CH.sub.2--Cl H H H
--SCH.sub.3 H 1104 --CO--C(CH.sub.3).sub.2--CH.sub.2--Cl H H H
--OCH.sub.3 H 1105 --CO--C(CH.sub.3).sub.2--CH.sub.2--Cl H H
--OCH.sub.3 --OH H 1106 --CO--C(CH.sub.3).sub.2--CH.sub.2--Cl H
--OCH.sub.3 --CH.sub.3 H H 1107
--CO--C(CH.sub.3).sub.2--CH.sub.2--Cl H H --CH.sub.2--CH.sub.3 H H
1108 --CO--C(CH.sub.3).sub.2--CH.sub.2--Cl H --OCH.sub.3
--CH(CH.sub.3).sub.2 H H 1109
--CO--C(CH.sub.3).sub.2--CH.sub.2--C-
l H H --C.sub.3H.sub.7-n H H 1110
--CO--C(CH.sub.3).sub.2--CH.sub.2- --Cl H H --OCH.sub.2--CH.sub.3 H
H 1111 --CO--C(CH.sub.3).sub.2--CH- .sub.2--Cl H H F H H 1112
--CO--C(CH.sub.3).sub.2--CH.sub.2--Cl H H Cl H H 1113
--CO--C(CH.sub.3).sub.2--CH.sub.2--Cl H H Br H H 1114
--CO--C(CH.sub.3).sub.2--CH.sub.2--Cl H H Cl Cl H 1115
--CO--C(CH.sub.3).sub.2--CH.sub.2--Cl H H OH OH OH 1116
--CO--C(CH.sub.3).sub.2--CH.sub.2--Cl H Cl Cl H Cl 1117
--CO--C(CH.sub.3).sub.2--CH.sub.2--Cl H H --CF.sub.3 H H 1118
--CO--C(CH.sub.3).sub.2--CH.sub.2--Cl H H --OCF.sub.3 H H 1119
--CO--C(CH.sub.3).sub.2--CH.sub.2--Cl H H --C.sub.2F.sub.5 H H 1120
--CO--C(CH.sub.3).sub.2--CH.sub.2--Cl H H --C.sub.4H.sub.9-tert H H
1121 --CO--C(CH.sub.3).sub.2--CH.sub.2--Cl H H --OC.sub.3H.sub.7-i
H H 1122 --CO--C(CH.sub.3).sub.2--CH.sub.2--Cl H H --SO--CH.sub.3 H
H 1123 --CO--C(CH.sub.3).sub.2--CH.sub.2--Cl H H
--SO.sub.2--CH.sub.3 H H 1124 --CO--C(CH.sub.3).sub.2--CH.sub.2--C-
l H H --NH--CH.sub.2--CH.sub.3 H H 1125
--CO--C(CH.sub.3).sub.2--CH- .sub.2--Cl H H
--O--CH.sub.2--CH.dbd.CH.sub.2 H H 1126
--CO--C(CH.sub.3).sub.2--CH.sub.2--Cl H H --O--CH.sub.2--C.dbd.CH H
H 1127 --CO--C(CH.sub.3).sub.2--CH.sub.2--Cl H H
--NH--CH.sub.2--CH.sub.- 2--NH--CH.sub.3 H H 1128
--CO--C(CH.sub.3).sub.2--CH.sub.2--Cl H H
--SO.sub.2--C.sub.2H.sub.5 H H 1129 --CO--C(CH.sub.3).sub.2--CH.su-
b.2--Cl H H --SO.sub.2--CH.sub.3 Cl H 1130 H H H F H H 1131
CH.sub.3 H H --OCF.sub.3 H H 1132 CH.sub.3 H H
--CH.sub.2--CH.sub.2--O--CH.sub.3 H H 1133 CH.sub.3 CH.sub.3 H
--SCH.sub.3 H H 1134 --CO--CH.sub.3 H H --SO.sub.2--CH.sub.3 Cl H
1135 --CO--CH(CH.sub.3)--C.sub.2H.sub.5 H H --C(.dbd.NOH)--CH.sub.3
H H 1136 --CO--C.sub.3F.sub.7-n H H --OCF.sub.3 H H 1137
--CO--C.sub.2F.sub.5 H H 240 H H 1138 --CO--CF.sub.3 H H
--CH.sub.2--CH.sub.3 H H 1139 --CO--C.sub.3H.sub.5-cycl H H
--SO.sub.2--CH.sub.3 H H 1140
--N.dbd.C(CH.sub.3)--N(CH.sub.3).sub.2 H
--CH(CH.sub.3)--O--CO--CH.sub.3 H H 1141
--N.dbd.CH--N(CH.sub.3).sub.2 H --OH H H 1143
--CO--C(CH.sub.3).sub.2--CH.sub.2--Cl H H --CH.sub.2--CN H H 1144
--CO--C(CH.sub.3).sub.2--CH.sub.2--Cl H H --CH--(CH.sub.3)--CN H H
1145 --CO--C(CH.sub.3).sub.2--CH.sub.2--Cl H H
--C(CH.sub.3).sub.2--CN H H 1146
--CO--C(CH.sub.3).sub.2--CH.sub.2--Cl H H
--CH--(C.sub.2H.sub.5)--CN H H 1147 --CO--C(CH.sub.3).sub.2--CH.su-
b.2--Cl H H --C(C.sub.2H.sub.5).sub.2--CN H H 1148
--CO--C(CH.sub.3).sub.2--CH.sub.2--Cl H H --CH.sub.2--CH.sub.2--CN
H H 1149 --CO--C(CH.sub.3).sub.2--CH.sub.2--Cl H H
--CH(CH.sub.3)--CH.sub.2--CN H H 1150 --CO--C(CH.sub.3).sub.2--CH.-
sub.2--Cl H H --CH.sub.2--CO.sub.2--CH.sub.3 H H 1151
--CO--C(CH.sub.3).sub.2--CH.sub.2--Cl H H
--CH(CH.sub.3)--CO.sub.2--CH.su- b.3 H H 1152 C.sub.2H.sub.5 H H
--CH.sub.2--CN H H 1153 C.sub.2H.sub.5 H H --CH--(CH.sub.3)--CN H H
1154 C.sub.2H.sub.5 H H --C(CH.sub.3).sub.2--CN H H 1155
C.sub.2H.sub.5 H H --CH--(C.sub.2H.sub.5)--CN H H 1156
C.sub.2H.sub.5 H H --C(C.sub.2H.sub.5).sub.2--CN H H 1157
C.sub.2H.sub.5 H H --CH.sub.2--CH.sub.2--CN H H 1158 C.sub.2H.sub.5
H H --CH(CH.sub.3)--CH.sub.2--CN H H 1159 C.sub.2H.sub.5 H H
--CH.sub.2--CO.sub.2--CH.sub.3 H H 1160 C.sub.2H.sub.5 H H
--CH(CH.sub.3)--CO.sub.2--CH.sub.3 H H 1161 CH.sub.3 H H
--CH.sub.2--CN H H 1162 CH.sub.3 H H --CH--(CH.sub.3)--CN H H 1163
CH.sub.3 H H --C(CH.sub.3).sub.2--CN H H 1164 CH.sub.3 H H
--CH--(C.sub.2H.sub.5)--CN H H 1165 CH.sub.3 H H
--C(C.sub.2H.sub.5).sub.2--CN H H 1166 CH.sub.3 H H
--CH.sub.2--CH.sub.2--CN H H 1167 CH.sub.3 H H
--CH(CH.sub.3)--CH.sub.2--CN H H 1168 CH.sub.3 H H
--CH.sub.2--CO.sub.2--CH.sub.3 H H 1169 CH.sub.3 H H
--CH(CH.sub.3)--CO.sub.2--CH.sub.3 H H 1170 CH.sub.3 CH.sub.3 H
--CH.sub.2--CN H H 1171 CH.sub.3 CH.sub.3 H --CH--(CH.sub.3)--CN H
H 1172 CH.sub.3 CH.sub.3 H --C(CH.sub.3).sub.2--CN H H 1173
CH.sub.3 CH.sub.3 H --CH--(C.sub.2H.sub.5)--CN H H 1174 CH.sub.3
CH.sub.3 H --C(C.sub.2H.sub.5).sub.2--CN H H 1175 CH.sub.3 CH.sub.3
H --CH.sub.2--CH.sub.2--CN H H 1176 CH.sub.3 CH.sub.3 H
--CH(CH.sub.3)--CH.sub.2--CN H H 1177 CH.sub.3 CH.sub.3 H
--CH.sub.2--CO.sub.2--CH.sub.3 H H 1178 CH.sub.3 CH.sub.3 H
--CH(CH.sub.3)--CO.sub.2--CH.sub.3 H H 1179 --CO--CH.sub.3 H H
--CH.sub.2--CN H H 1180 --CO--CH.sub.3 H H --CH--(CH.sub.3)--CN H H
1181 --CO--CH.sub.3 H H --C(CH.sub.3).sub.2--CN H H 1182
--CO--CH.sub.3 H H --CH--(C.sub.2H.sub.5)--CN H H 1183
--CO--CH.sub.3 H H --C(C.sub.2H.sub.5).sub.2--CN H H 1184
--CO--CH.sub.3 H H --CH.sub.2--CH.sub.2--CN H H 1185 --CO--CH.sub.3
H H --CH(CH.sub.3)--CH.sub.2--CN H H 1186 --CO--CH.sub.3 H H
--CH.sub.2--CO.sub.2--CH.sub.3 H H 1187 --CO--CH.sub.3 H H
--CH(CH.sub.3)--CO.sub.2--CH.sub.3 H H 1188 --CO--C.sub.2H.sub.5 H
H --CH.sub.2--CN H H 1189 --CO--C.sub.2H.sub.5 H H
--CH--(CH.sub.3)--CN H H 1190 --CO--C.sub.2H.sub.5 H H
--C(CH.sub.3).sub.2--CN H H 1191 --CO--C.sub.2H.sub.5 H H
--CH--(C.sub.2H.sub.5)--CN H H 1192 --CO--C.sub.2H.sub.5 H H
--C(C.sub.2H.sub.5).sub.2--CN H H 1193 --CO--C.sub.2H.sub.5 H H
--CH.sub.2--CH.sub.2--CN H H 1194 --CO--C.sub.2H.sub.5 H H
--CH(CH.sub.3)--CH.sub.2--CN H H 1195 --CO--C.sub.2H.sub.5 H H
--CH.sub.2--CO.sub.2--CH.sub.3 H H 1196 --CO--C.sub.2H.sub.5 H H
--CH(CH.sub.3)--CO.sub.2--CH.sub.3 H H 1197
--CO--CH(CH.sub.3)--C.sub.2H.sub.5 H H --CH.sub.2--CN H H 1198
--CO--CH(CH.sub.3)--C.sub.2H.sub.5 H H --CH--(CH.sub.3)--CN H H
1199 --CO--CH(CH.sub.3)--C.sub.2H.sub.5 H H --C(CH.sub.3).sub.2--CN
H H 1200 --CO--CH(CH.sub.3)--C.sub.2H.sub.5 H H
--CH--(C.sub.2H.sub.5)--CN H H 1201 --CO--CH(CH.sub.3)--C.sub.2H.s-
ub.5 H H --C(C2IT5).sub.2--CN H H 1202
--CO--CH(CH.sub.3)--C.sub.2H- .sub.5 H H --CH.sub.2--CH.sub.2--CN H
H 1203 --CO--CH(CH.sub.3)--C.sub.2H.sub.5 H H
--CH(CH.sub.3)--CH.sub.2--CN H H 1204
--CO--CH(CH.sub.3)--C.sub.2H.sub.5 H H --CH.sub.2--CO.sub.2--CH-
.sub.3 H H 1205 --CO--CH(CH.sub.3)--C.sub.2H.sub.5 H H
--CH(CH.sub.3)--CO.sub.2--CH.sub.3 H H 1206 --CO--C.sub.3F.sub.7-n
H H --CH.sub.2--CN H H 1207 --CO--C.sub.3F.sub.7-n H H
--CH--(CH.sub.3)--CN H H 1208 --CO--C.sub.3F.sub.7-n H H
--C(CH.sub.3).sub.2--CN H H 1209 --CO--C.sub.3F.sub.7-n H H
--CH--(C.sub.2H.sub.5)--CN H H 1210 --CO--C.sub.3F.sub.7-n H H
--C(C.sub.2H.sub.5).sub.2--CN H H 1211 --CO--C.sub.3F.sub.7-n H H
--CH.sub.2--CH.sub.2--CN H H 1212 --CO--C.sub.3F.sub.7-n H H
--CH(CH.sub.3)--CH.sub.2--CN H H 1213 --CO--C.sub.3F.sub.7-n H H
--CH.sub.2--CO.sub.2--CH.sub.3 H H 1214 --CO--C.sub.3F.sub.7-n H H
--CH(CH.sub.3)--CO.sub.2--CH.sub.3 H H 1215
--CO--CH.sub.2--O--CO--CH.sub.3 H H --CH.sub.2--CN H H 1216
--CO--CH.sub.2--O--CO--CH.sub.3 H H --CH--(CH.sub.3)--CN H H 1217
--CO--CH.sub.2--O--CO--CH.sub.3 H H --C(CH.sub.3).sub.2--CN H H
1218 --CO--CH.sub.2--O--CO--CH.sub.3 H H --CH--(C.sub.2H.sub.5)--CN
H H 1219 --CO--CH.sub.2--O--CO--CH.sub.3 H H
--C(C.sub.2H.sub.5).sub.2--- CN H H 1220
--CO--CH.sub.2--O--CO--CH.sub.3 H H --CH.sub.2--CH.sub.2--CN H H
1221 --CO--CH.sub.2--O--CO--CH.sub.3 H H
--CH(CH.sub.3)--CH.sub.2--CN H H 1222 --CO--CH.sub.2--O--CO--C-
H.sub.3 H H --CH.sub.2--CO.sub.2--CH.sub.3 H H 1223
--CO--CH.sub.2--O--CO--CH.sub.3 H H
--CH(CH.sub.3)--CO.sub.2--CH.sub.3 H H 1224 --CO--C.sub.2F.sub.5 H
H --CH.sub.2--CN H H 1225 --CO--C.sub.2F.sub.5 H H
--CH--(CH.sub.3)--CN H H 1226 --CO--C.sub.2F.sub.5 H H
--C(CH.sub.3).sub.2--CN H H 1227 --CO--C.sub.2F.sub.5 H H
--CH--(C.sub.2H.sub.5)--CN H H 1228 --CO--C.sub.2F.sub.5 H H
--C(C.sub.2H.sub.5).sub.2--CN H H 1229 --CO--C.sub.2F.sub.5 H H
--CH.sub.2--CH.sub.2--CN H H 1230 --CO--C.sub.2F.sub.5 H H
--CH(CH.sub.3)--CH.sub.2--CN H H 1231 --CO--C.sub.2F.sub.5 H H
--CH.sub.2--CO.sub.2--CH.sub.3 H H 1232 --CO--C.sub.2F.sub.5 H H
--CH(CH.sub.3)--CO.sub.2--CH.sub.3 H H 1233 --CO--CF.sub.3 H H
--CH.sub.2--CN H H 1234 --CO--CF.sub.3 H H --CH--(CH.sub.3)--CN H H
1235 --CO--CF.sub.3 H H --C(CH.sub.3).sub.2--CN H H 1236
--CO--CF.sub.3 H H --CH--(C.sub.2H.sub.5)--CN H H 1237
--CO--CF.sub.3 H H --C(C.sub.2H.sub.5).sub.2--CN H H 1238
--CO--CF.sub.3 H H --CH.sub.2--CH.sub.2--CN H H 1239 --CO--CF.sub.3
H H --CH(CH.sub.3)--CH.sub.2--CN H H 1240 --CO--CF.sub.3 H H
--CH.sub.2--CO.sub.2--CH.sub.3 H H 1241 --CO--CF.sub.3 H H
--CH(CH.sub.3)--CO.sub.2--CH.sub.3 H H 1243 --(CH.sub.2).sub.4-- H
--CH.sub.2--CN H H 1244 --(CH.sub.2).sub.4-- H --CH--(CH.sub.3)--CN
H H 1245 --(CH.sub.2).sub.4-- H --C(CH.sub.3).sub.2--CN H H 1246
--(CH.sub.2).sub.4-- H --CH--(C.sub.2H.sub.5)--CN H H 1247
--(CH.sub.2).sub.4-- H --C(C.sub.2H.sub.5).sub.2--CN H H 1248
--(CH.sub.2).sub.4-- H --CH.sub.2--CH.sub.2--CN H H 1249
--(CH.sub.2).sub.4-- H --CH(CH.sub.3)--CH.sub.2--CN H H 1250
--(CH.sub.2).sub.4-- H --CH.sub.2--CO.sub.2--CH.sub.3 H H 1251
--(CH.sub.2).sub.4-- H --CH(CH.sub.3)--CO.sub.2--CH.sub.3 H H 1252
--N.dbd.C(CH.sub.3)--N(CH.sub.3).sub.2 H --CH.sub.2--CN H H 1253
--N.dbd.C(CH.sub.3)--N(CH.sub.3).sub.2 H --CH--(CH.sub.3)--CN H H
1254 --N.dbd.C(CH.sub.3)--N(CH.sub.3).sub.2 H
--C(CH.sub.3).sub.2--CN H H 1255
--N.dbd.C(CH.sub.3)--N(CH.sub.3).sub.2 H --CH--(C.sub.2H.sub.5)--CN
H H 1256 --N.dbd.C(CH.sub.3)--N(CH.sub.- 3).sub.2 H
--C(C.sub.2H.sub.5).sub.2--CN H H 1257
--N.dbd.C(CH.sub.3)--N(CH.sub.3).sub.2 H --CH.sub.2--CH.sub.2--CN H
H 1258 --N.dbd.C(CH.sub.3)--N(CH.sub.3).sub.2 H
--CH(CH.sub.3)--CH.sub.2- --CN H H 1259
--N.dbd.C(CH.sub.3)--N(CH.sub.3).sub.2 H
--CH.sub.2--CO.sub.2--CH.sub.3 H H 1260 --N.dbd.C(CH.sub.3)--N(CH.-
sub.3).sub.2 H --CH(CH.sub.3)--CO.sub.2--CH.sub.3 H H 1261
--N.dbd.CH--N(CH.sub.3).sub.2 H --CH.sub.2--CN H H 1262
--N.dbd.CH--N(CH.sub.3).sub.2 H --CH--(CH.sub.3)--CN H H 1263
--N.dbd.CH--N(CH.sub.3).sub.2 H --C(CH.sub.3).sub.2--CN H H 1264
--N.dbd.CH--N(CH.sub.3).sub.2 H --CH--(C.sub.2H.sub.5)--CN H H 1265
--N.dbd.CH--N(CH.sub.3).sub.2 H --C(C.sub.2H.sub.5).sub.2--CN H H
1266 --N.dbd.CH--N(CH.sub.3).sub.2 H --CH.sub.2--CH.sub.2--CN H H
1267 --N.dbd.CH--N(CH.sub.3).sub.2 H --CH(CH.sub.3)--CH.sub.2--CN H
H 1268 --N.dbd.CH--N(CH.sub.3).sub.2 H
--CH.sub.2--CO.sub.2--CH.sub.- 3 H H 1269
--N.dbd.CH--N(CH.sub.3).sub.2 H --CH(CH.sub.3)--CO.sub.2-
--CH.sub.3 H H 1270 --CO--C.sub.3H.sub.5-cycl H H --CH.sub.2--CN H
H 1271 --CO--C.sub.3H.sub.5-cycl H H --CH--(CH.sub.3)--CN H H 1272
--CO--C.sub.3H.sub.5-cycl H H --C(CH.sub.3).sub.2--CN H H 1273
--CO--C.sub.3H.sub.5-cycl H H --CH--(C.sub.2H.sub.5)--CN H H 1274
--CO--C.sub.3H.sub.5-cycl H H --C(C.sub.2H.sub.5).sub.2--CN H H
1275 --CO--C.sub.3H.sub.5-cycl H H --CH.sub.2--CH.sub.2--CN H H
1276 --CO--C.sub.3H.sub.5-cycl H H --CH(CH.sub.3)--CH.sub.2--CN H H
1277 --CO--C.sub.3H.sub.5-cycl H H --CH.sub.2--CO.sub.2--CH.sub.3 H
H 1278 --CO--C.sub.3H.sub.5-cyc- l H H
--CH(CH.sub.3)--CO.sub.2--CH.sub.3 H H 1279
--CH.sub.2--CH.sub.2--O--CH.sub.3 H H --CH.sub.2--O--CH.sub.3 H H
1280 --CH.sub.2--CH.sub.2--O--CH.sub.3 H H --NH--CO--CH.sub.3 H H
1281 --CH.sub.2--CH.sub.2--O--CH.sub.3 H H
--CH.sub.2--NH--CO--CH.sub.3 H H 1282
--CH.sub.2--CH.sub.2--O--CH.sub.3 H H
--CH(CH.sub.3)--NH--CO--CH.sub.3 H H 1283 --CH.sub.2--CH.sub.2--O--
-CH.sub.3 H H --C(CH.sub.3).sub.2--NH--CO--CH.sub.3 H H 1284
--CH.sub.2--CH.sub.2--O--CH.sub.3 H H --CH(CH.sub.3)--O--CH.sub.3 H
H 1285 --CH.sub.2--CH.sub.2--O--CH.sub.3 H H
--C(CH.sub.3).sub.2--O--CH.- sub.3 H H 1286
--CH.sub.2--CH.sub.2--O--CH.sub.3 H H
--CH(CH.sub.3)--O--CO--CH.sub.3 H H 1287 --CH.sub.2--CH.sub.2--O---
CH.sub.3 H H --CH.sub.2--O--CO--CH.sub.3 H H 1288
--CH.sub.2--CH.sub.2--O--CH.sub.3 H H
--C(CH.sub.3).sub.2--O--CO--CH.sub.- 3 H H 1289
--CH.sub.2--CH.sub.2--O--CH.sub.3 H H --CH.sub.2--CH.sub.2--O--H H
H 1290 --CH.sub.2--CH.sub.2--O--CH.su- b.3 H H
--CH.sub.2--CH.sub.2--O--CH.sub.3 H H 1291
--CH.sub.2--CH.sub.2--O--CH.sub.3 H H 241 H H 1292
--CH.sub.2--CH.sub.2--O--CH.sub.3 H H 242 H H 1293
--CH.sub.2--CH.sub.2--O--CH.sub.3 H H 243 H H 1294
--CH.sub.2--CH.sub.2--O--CH.sub.3 H H 244 H H 1295
--CH.sub.2--CH.sub.2--O--CH.sub.3 H H 245 H H 1296
--CH.sub.2--CH.sub.2--O--CH.sub.3 H H 246 H H 1297
--CH.sub.2--CH.sub.2--O--CH.sub.3 H H 247 H H 1298
--CH.sub.2--CH.sub.2--O--CH.sub.3 H H 248 H H 1299
--CH.sub.2--CH.sub.2--O--CH.sub.3 H H 249 H H 1300
--CH.sub.2--CH.sub.2--O--CH.sub.3 H H 250 H H 1301
--CH.sub.2--CH.sub.2--O--CH.sub.3 H H 251 H H 1302
--CH.sub.2--CH.sub.2--O--CH.sub.3 H H 252 H H 1303
--CH.sub.2--CH.sub.2--O--CH.sub.3 H H H H H 1304
--CH.sub.2--CH.sub.2--O--CH.sub.3 H H CN H H 1305
--CH.sub.2--CH.sub.2--O--CH.sub.3 H H --C(CH.sub.3).sub.2--OH H H
1306 --CH.sub.2--CH.sub.2--O--CH.sub.3 H H --CH.sub.2--OH H H 1307
--CH.sub.2--CH.sub.2--O--CH.sub.3 H H --CO--CH.sub.3 H H 1308
--CH.sub.2--CH.sub.2--O--CH.sub.3 H H --C(.dbd.NOH)--CH.sub.3 H H
1309 --CH.sub.2--CH.sub.2--O--CH.sub.3 H H --CH(OH)--CH.sub.3 H H
1310 --CH.sub.2--CH.sub.2--O--CH.sub.3 H H (3) --CO--O--CH.sub.2--
(4) H 1311 --CH.sub.2--CH.sub.2--O--CH.sub.3 H H
--CH.sub.2--O--CO--CH.s- ub.3 H H 1312
--CH.sub.2--CH.sub.2--O--CH.sub.3 H H
--C(.dbd.NO--CH.sub.3)--CH.sub.3 H H 1313 --CH.sub.2--CH.sub.2--O--
-CH.sub.3 H H --CO--O--CH.sub.3 H H 1314
--CH.sub.2--CH.sub.2--O--C- H.sub.3 H H
--NH--CO--C.sub.3H.sub.5-cycl. H H 1315
--CH.sub.2--CH.sub.2--O--CH.sub.3 H H --CO--CH.sub.3 Cl H 1316
--CH.sub.2--CH.sub.2--O--CH.sub.3 H H --OH H H 1317
--CH.sub.2--CH.sub.2--O--CH.sub.3 H H --OH --OCH.sub.3 H 1318
--CH.sub.2--CH.sub.2--O--CH.sub.3 H H --OCH.sub.3 H --OCH.sub.3
1319 --CH.sub.2--CH.sub.2--O--CH.sub.3 H H --SCH.sub.3 H H 1320
--CH.sub.2--CH.sub.2--O--CH.sub.3 H H --OCH.sub.3 H H 1321
--CH.sub.2--CH.sub.2--O--CH.sub.3 H H --OCH.sub.3 --OCH.sub.3
--OCH.sub.3 1322 --CH.sub.2--CH.sub.2--O--CH.sub.3 H H --OH
--OCH.sub.3 --OCH.sub.3 1323 --CH.sub.2--CH.sub.2--O--CH.sub.3 H H
H --SCH.sub.3 H 1324 --CH.sub.2--CH.sub.2--O--CH.sub.3 H H H
--OCH.sub.3 H 1325 --CH.sub.2--CH.sub.2--O--CH.sub.3 H H
--OCH.sub.3 --OH H 1326 --CH.sub.2--CH.sub.2--O--CH.sub.3 H
--OCH.sub.3 --CH.sub.3 H H 1327 --CH.sub.2--CH.sub.2--O--CH.sub.3 H
H H H 1328 --CH.sub.2--CH.sub.2--O--CH.sub.3 H --OCH.sub.3
--CH(CH.sub.3).sub.2 H H 1329 --CH.sub.2--CH.sub.2--O--CH.sub.3 H H
--C.sub.3H.sub.7-n H H 1330 --CH.sub.2--CH.sub.2--O--CH.sub.3 H H
--OCH.sub.2--CH.sub.3 H H 1331 --CH.sub.2--CH.sub.2--O--CH.sub.3 H
H F H H 1332 --CH.sub.2--CH.sub.2--O--CH.sub.3 H H Cl H H 1333
--CH.sub.2--CH.sub.2--O--CH.sub.3 H H Br H H 1334
--CH.sub.2--CH.sub.2--O--CH.sub.3 H H Cl Cl H 1335
--CH.sub.2--CH.sub.2--O--CH.sub.3 H H OH OH OH 1336
--CH.sub.2--CH.sub.2--O--CH.sub.3 H Cl Cl H Cl 1337
--CH.sub.2--CH.sub.2--O--CH.sub.3 H H --CF.sub.3 H H 1338
--CH.sub.2--CH.sub.2--O--CH.sub.3 H H --OCF.sub.3 H H 1339
--CH.sub.2--CH.sub.2--O--CH.sub.3 H H --C.sub.2F.sub.5 H H 1340
--CH.sub.2--CH.sub.2--O--CH.sub.3 H H --C.sub.4H.sub.9-tert H H
1341 --CH.sub.2--CH.sub.2--O--CH.sub.3 H H --OC.sub.3H.sub.7-i H H
1343 --CH.sub.2--CH.sub.2--O--CH.sub.3 H H --SO--CH.sub.3 H H 1344
--CH.sub.2--CH.sub.2--O--CH.sub.3 H H --SO.sub.2--CH.sub.3 H H 1345
--CH.sub.2--CH.sub.2--O--CH.sub.3 H H --NH--CH.sub.2--CH.sub.3 H H
1346 --CH.sub.2--CH.sub.2--O--CH.sub.3 H H
--O--CH.sub.2--CH.dbd.CH.- sub.2 H H 1347
--CH.sub.2--CH.sub.2--O--CH.sub.3 H H --O--CH.sub.2--C.dbd.CH H H
1348 --CH.sub.2--CH.sub.2--O--CH.sub.3 H H
--NH--CH.sub.2--CH.sub.2--NH--CH.sub.3 H H 1349
--CH.sub.2--CH.sub.2--O--CH.sub.3 H H --SO.sub.2--C.sub.2H.sub.5 H
H 1350 --CH.sub.2--CH.sub.2--O--CH.sub.3 H H --SO.sub.2--CH.sub.3
Cl H 1351 --CH.sub.2--CH.sub.2--O--CH.sub.3 H H --CH.sub.2--CN H H
1352 --CH.sub.2--CH.sub.2--O--CH.sub.3 H H --CH--(CH.sub.3)--CN H H
1353 --CH.sub.2--CH.sub.2--O--CH.sub.3 H H --C(CH.sub.3).sub.2--CN
H H
1354 --CH.sub.2--CH.sub.2--O--CH.sub.3 H H
--CH--(C.sub.2H.sub.5)--C- N H H 1355
--CH.sub.2--CH.sub.2--O--CH.sub.3 H H --C(C.sub.2H.sub.5).sub.2--CN
H H 1356 --CH.sub.2--CH.sub.2--O--CH- .sub.3 H H
--CH.sub.2--CH.sub.2--CN H H 1357 --CH.sub.2--CH.sub.2--O--CH.sub.3
H H --CH(CH.sub.3)--CH.sub.2--CN H H 1358
--CH.sub.2--CH.sub.2--O--CH.sub.3 H H --CH.sub.2--CO.sub.2--CH.s-
ub.3 H H 1359 --CH.sub.2--CH.sub.2--O--CH.sub.3 H H
--CH(CH.sub.3)--CO.sub.2--CH.sub.3 H H 1360
--CH(CH.sub.3)--CH.sub.2--O--CH.sub.3 H H --CH.sub.2--O--CH.sub.3 H
H 1361 --CH(CH.sub.3)--CH.sub.2--O--CH.sub.3 H H --NH--CO--CH.sub.3
H H 1362 --CH(CH.sub.3)--CH.sub.2--O--CH.sub.3 H H
--CH.sub.2--NH--CO--CH.sub.3 H H 1363 --CH(CH.sub.3)--CH.sub.2--O--
-CH.sub.3 H H --CH(CH.sub.3)--NH--CO--CH.sub.3 H H 1364
--CH(CH.sub.3)--CH.sub.2--O--CH.sub.3 H H
--C(CH.sub.3).sub.2--NH--CO--CH- .sub.3 H H 1365
--CH(CH.sub.3)--CH.sub.2--O--CH.sub.3 H H
--CH(CH.sub.3)--O--CH.sub.3 H H 1366 --CH(CH.sub.3)--CH.sub.2--O---
CH.sub.3 H H --C(CH.sub.3).sub.2--O--CH.sub.3 H H 1367
--CH(CH.sub.3)--CH.sub.2--O--CH.sub.3 H H
--CH(CH.sub.3)--O--CO--CH.sub.3 H H 1368
--CH(CH.sub.3)--CH.sub.2--O--CH.sub.3 H H
--CH.sub.2--O--CO--CH.sub.3 H H 1369 --CH(CH.sub.3)--CH.sub.2--O---
CH.sub.3 H H --C(CH.sub.3).sub.2--O--CO--CH.sub.3 H H 1370
--CH(CH.sub.3)--CH.sub.2--O--CH.sub.3 H H
--CH.sub.2--CH.sub.2--O--H H H 1371
--CH(CH.sub.3)--CH.sub.2--O--CH.sub.3 H H
--CH.sub.2--CH.sub.2--O--CH.sub.3 H H 1372
--CH(CH.sub.3)--CH.sub.2--O--CH.sub.3 H H 253 H H 1373
--CH(CH.sub.3)--CH.sub.2--O--CH.sub.3 H H 254 H H 1374
--CH(CH.sub.3)--CH.sub.2--O--CH.sub.3 H H 255 H H 1375
--CH(CH.sub.3)--CH.sub.2--O--CH.sub.3 H H 256 H H 1376
--CH(CH.sub.3)--CH.sub.2--O--CH.sub.3 H H 257 H H 1377
--CH(CH.sub.3)--CH.sub.2--O--CH.sub.3 H H 258 H H 1378
--CH(CH.sub.3)--CH.sub.2--O--CH.sub.3 H H 259 H H 1379
--CH(CH.sub.3)--CH.sub.2--O--CH.sub.3 H H 260 H H 1380
--CH(CH.sub.3)--CH.sub.2--O--CH.sub.3 H H 261 H H 1381
--CH(CH.sub.3)--CH.sub.2--O--CH.sub.3 H H 262 H H 1382
--CH(CH.sub.3)--CH.sub.2--O--CH.sub.3 H H 263 H H 1383
--CH(CH.sub.3)--CH.sub.2--O--CH.sub.3 H H 264 H H 1384
--CH(CH.sub.3)--CH.sub.2--O--CH.sub.3 H H H H H 1385
--CH(CH.sub.3)--CH.sub.2--O--CH.sub.3 H H CN H H 1386
--CH(CH.sub.3)--CH.sub.2--O--CH.sub.3 H H --C(CH.sub.3).sub.2--OH H
H 1387 --CH(CH.sub.3)--CH.sub.2--O--CH.sub.3 H H --CH.sub.2--OH H H
1388 --CH(CH.sub.3)--CH.sub.2--O--CH.sub.3 H H --CO--CH.sub.3 H H
1389 --CH(CH.sub.3)--CH.sub.2--O--CH.sub.3 H H
--C(.dbd.NOH)--CH.sub.3 H H 1390
--CH(CH.sub.3)--CH.sub.2--O--CH.sub.3 H H --CH(OH)--CH.sub.3 H H
1391 --CH(CH.sub.3)--CH.sub.2--O--CH.sub.3 H H (3)
--CO--O--CH.sub.2-- (4) H 1392 --CH(CH.sub.3)--CH.sub.2---
O--CH.sub.3 H H --CH.sub.2--O--CO--CH.sub.3 H H 1393
--CH(CH.sub.3)--CH.sub.2--O--CH.sub.3 H H
--C(.dbd.NO--CH.sub.3)--CH.sub.- 3 H H 1394
--CH(CH.sub.3)--CH.sub.2--O--CH.sub.3 H H --CO--O--CH.sub.3 H H
1395 --CH(CH.sub.3)--CH.sub.2--O--CH.sub.3 H H
--NH--CO--C.sub.3H.sub.5-cycl. H H 1396 --CH(CH.sub.3)--CH.sub.2-
--O--CH.sub.3 H H --CO--CH.sub.3 Cl H 1397
--CH(CH.sub.3)--CH.sub.2- --O--CH.sub.3 H H --OH H H 1398
--CH(CH.sub.3)--CH.sub.2--O--CH.sub- .3 H H --OH --OCH.sub.3 H 1399
--CH(CH.sub.3)--CH.sub.2--O--CH.sub.- 3 H H --OCH.sub.3 H
--OCH.sub.3 1400 --CH(CH.sub.3)--CH.sub.2--O--C- H.sub.3 H H
--SCH.sub.3 H H 1401 --CH(CH.sub.3)--CH.sub.2--O--CH.su- b.3 H H
--OCH.sub.3 H H 1402 --CH(CH.sub.3)--CH.sub.2--O--CH.sub.3 H H
--OCH.sub.3 --OCH.sub.3 --OCH.sub.3 1403
--CH(CH.sub.3)--CH.sub.2--O--CH.sub.3 H H --OH --OCH.sub.3
--OCH.sub.3 1404 --CH(CH.sub.3)--CH.sub.2--O--CH.sub.3 H H H
--SCH.sub.3 H 1405 --CH(CH.sub.3)--CH.sub.2--O--CH.sub.3 H H H
--OCH.sub.3 H 1406 --CH(CH.sub.3)--CH.sub.2--O--CH.sub.3 H H
--OCH.sub.3 --OH H 1407 --CH(CH.sub.3)--CH.sub.2--O--CH.sub.3 H
--OCH.sub.3 --CH.sub.3 H H 1408
--CH(CH.sub.3)--CH.sub.2--O--CH.sub.3 H H --CH.sub.2--CH.sub.3 H H
1409 --CH(CH.sub.3)--CH.sub.2--O--CH.sub.3 H --OCH.sub.3
--CH(CH.sub.3).sub.2 H H 1410 --CH(CH.sub.3)--CH.sub.2--O--CH.sub.-
3 H H --C.sub.3H.sub.7-n H H 1411
--CH(CH.sub.3)--CH.sub.2--O--CH.s- ub.3 H H --OCH.sub.2--CH.sub.3 H
H 1412 --CH(CH.sub.3)--CH.sub.2--O- --CH.sub.3 H H F H H 1413
--CH(CH.sub.3)--CH.sub.2--O--CH.sub.3 H H Cl H H 1414
--CH(CH.sub.3)--CH.sub.2--O--CH.sub.3 H H Br H H 1415
--CH(CH.sub.3)--CH.sub.2--O--CH.sub.3 H H Cl Cl H 1416
--CH(CH.sub.3)--CH.sub.2--O--CH.sub.3 H H OH OH OH 1417
--CH(CH.sub.3)--CH.sub.2--O--CH.sub.3 H Cl Cl H Cl 1418
--CH(CH.sub.3)--CH.sub.2--O--CH.sub.3 H H --CF.sub.3 H H 1419
--CH(CH.sub.3)--CH.sub.2--O--CH.sub.3 H H --OCF.sub.3 H H 1420
--CH(CH.sub.3)--CH.sub.2--O--CH.sub.3 H H --C.sub.2F.sub.5 H H 1421
--CH(CH.sub.3)--CH.sub.2--O--CH.sub.3 H H --C.sub.4H.sub.9-tert H H
1422 --CH(CH.sub.3)--CH.sub.2--O--CH.sub.3 H H --OC.sub.3H.sub.7-i
H H 1423 --CH(CH.sub.3)--CH.sub.2--O--CH.sub.3 H H --SO--CH.sub.3 H
H 1424 --CH(CH.sub.3)--CH.sub.2--O--CH.sub.3 H H
--SO.sub.2--CH.sub.3 H H 1425 --CH(CH.sub.3)--CH.sub.2--O--CH.sub.-
3 H H --NH--CH.sub.2--CH.sub.3 H H 1426
--CH(CH.sub.3)--CH.sub.2--O- --CH.sub.3 H H
--O--CH.sub.2--CH.dbd.CH.sub.2 H H 1427
--CH(CH.sub.3)--CH.sub.2--O--CH.sub.3 H H --O--CH.sub.2--C.dbd.CH H
H 1428 --CH(CH.sub.3)--CH.sub.2--O--CH.sub.3 H H
--NH--CH.sub.2--CH.sub.- 2--NH--CH.sub.3 H H 1429
--CH(CH.sub.3)--CH.sub.2--O--CH.sub.3 H H
--SO.sub.2--C.sub.2H.sub.5 H H 1430 --CH(CH.sub.3)--CH.sub.2--O--C-
H.sub.3 H H --SO.sub.2--CH.sub.3 Cl H 1431
--CH(CH.sub.3)--CH.sub.2- --O--CH.sub.3 H H --CH.sub.2--CN H H 1432
--CH(CH.sub.3)--CH.sub.2-- -O--CH.sub.3 H H --CH--(CH.sub.3)--CN H
H 1433 --CH(CH.sub.3)--CH.sub.2--O--CH.sub.3 H H
--C(CH.sub.3).sub.2--CN H H 1434
--CH(CH.sub.3)--CH.sub.2--O--CH.sub.3 H H --CH--(C.sub.2H.sub.5)--
-CN H H 1435 --CH(CH.sub.3)--CH.sub.2--O--CH.sub.3 H H
--C(C.sub.2H.sub.5).sub.2--CN H H 1436 --CH(CH.sub.3)--CH.sub.2--O-
--CH.sub.3 H H --CH.sub.2--CH.sub.2--CN H H 1437
--CH(CH.sub.3)--CH.sub.2--O--CH.sub.3 H H
--CH(CH.sub.3)--CH.sub.2--CN H H 1438
--CH(CH.sub.3)--CH.sub.2--O--CH.sub.3 H H
--CH.sub.2--CO.sub.2--CH.sub.3 H H 1439 --CH(CH.sub.3)--CH.sub.2---
O--CH.sub.3 H H --CH(CH.sub.3)--CO.sub.2--CH.sub.3 H H 1440
--CH.sub.2--CH.sub.2--O--CH.sub.2--CH.sub.2-- H
--CH.sub.2--O--CH.sub.3 H H 1441 --CH.sub.2--CH.sub.2--O--CH.sub.2-
--CH.sub.2-- H --NH--CO--CH.sub.3 H H 1443
--CH.sub.2--CH.sub.2--O-- -CH.sub.2--CH.sub.2-- H
--CH.sub.2--NH--CO--CH.sub.3 H H 1444
--CH.sub.2--CH.sub.2--O--CH.sub.2--CH.sub.2-- H
--CH(CH.sub.3)--NH--CO--C- H.sub.3 H H 1445
--CH.sub.2--CH.sub.2--O--CH.sub.2--CH.sub.2-- H
--C(CH.sub.3).sub.2--NH--CO--CH.sub.3 H H 1446
--CH.sub.2--CH.sub.2--O--CH.sub.2--CH.sub.2-- H
--CH(CH.sub.3)--O--CH.sub- .3 H H 1447
--CH.sub.2--CH.sub.2--O--CH.sub.2--CH.sub.2-- H
--C(CH.sub.3).sub.2--O--CH.sub.3 H H 1448 --CH.sub.2--CH.sub.2--O--
-CH.sub.2--CH.sub.2-- H --CH(CH.sub.3)--O--CO--CH.sub.3 H H 1449
--CH.sub.2--CH.sub.2--O--CH.sub.2--CH.sub.2-- H
--CH.sub.2--O--CO--CH.sub- .3 H H 1450
--CH.sub.2--CH.sub.2--O--CH.sub.2--CH.sub.2-- H
--C(CH.sub.3).sub.2--O--CO--CH.sub.3 H H 1451
--CH.sub.2--CH.sub.2--O--CH.sub.2--CH.sub.2-- H
--CH.sub.2--CH.sub.2--O--- H H H 1452
--CH.sub.2--CH.sub.2--O--CH.sub.2--CH.sub.2-- H
--CH.sub.2--CH.sub.2--O--CH.sub.3 H H 1453
--CH.sub.2--CH.sub.2--O--CH.sub.2--CH.sub.2-- H 265 H H 1454
--CH.sub.2--CH.sub.2--O--CH.sub.2--CH.sub.2-- H 266 H H 1455
--CH.sub.2--CH.sub.2--O--CH.sub.2--CH.sub.2-- H 267 H H 1456
--CH.sub.2--CH.sub.2--O--CH.sub.2--CH.sub.2-- H 268 H H 1457
--CH.sub.2--CH.sub.2--O--CH.sub.2--CH.sub.2-- H 269 H H 1458
--CH.sub.2--CH.sub.2--O--CH.sub.2--CH.sub.2-- H 270 H H 1459
--CH.sub.2--CH.sub.2--O--CH.sub.2--CH.sub.2-- H 271 H H 1460
--CH.sub.2--CH.sub.2--O--CH.sub.2--CH.sub.2-- H 272 H H 1461
--CH.sub.2--CH.sub.2--O--CH.sub.2--CH.sub.2-- - H 273 H H 1462
--CH.sub.2--CH.sub.2--O--CH.sub.2--CH.sub- .2-- H 274 H H 1463
--CH.sub.2--CH.sub.2--O--CH.sub.2--CH.- sub.2-- H 275 H H 1464
--CH.sub.2--CH.sub.2--O--CH.sub.2--- CH.sub.2-- H 276 H H 1465
--CH.sub.2--CH.sub.2--O--CH.sub.- 2--CH.sub.2-- H H H H 1466
--CH.sub.2--CH.sub.2--O--CH.sub.2--CH.su- b.2-- H CN H H 1467
--CH.sub.2--CH.sub.2--O--CH.sub.2--CH.sub.2-- H
--C(CH.sub.3).sub.2--OH H H 1468 --CH.sub.2--CH.sub.2--O--CH.sub.2-
--CH.sub.2-- H --CH.sub.2--OH H H 1469
--CH.sub.2--CH.sub.2--O--CH.- sub.2--CH.sub.2-- H --CO--CH.sub.3 H
H 1470 --CH.sub.2--CH.sub.2--O- --CH.sub.2--CH.sub.2-- H
--C(.dbd.NOH)--CH.sub.3 H H 1471
--CH.sub.2--CH.sub.2--O--CH.sub.2--CH.sub.2-- H --CH(OH)--CH.sub.3
H H 1472 --CH.sub.2--CH.sub.2--O--CH.sub.2--CH.sub.2-- H (3)
--CO--O--CH.sub.2-- (4) H 1473 --CH.sub.2--CH.sub.2--O--CH.sub.2--
-CH.sub.2-- H --CH.sub.2--O--CO--CH.sub.3 H H 1474
--CH.sub.2--CH.sub.2--O--CH.sub.2--CH.sub.2-- H
--C(.dbd.NO--CH.sub.3)--C- H.sub.3 H H 1475
--CH.sub.2--CH.sub.2--O--CH.sub.2--CH.sub.2-- H --CO--O--CH.sub.3 H
H 1476 --CH.sub.2--CH.sub.2--O--CH.sub.2--CH.s- ub.2-- H
--NH--CO--C.sub.3H.sub.5-cycl. H H 1477
--CH.sub.2--CH.sub.2--O--CH.sub.2--CH.sub.2-- H --CO--CH.sub.3 Cl H
1478 --CH.sub.2--CH.sub.2--O--CH.sub.2--CH.sub.2-- H --OH H H 1479
--CH.sub.2--CH.sub.2--O--CH.sub.2--CH.sub.2-- H --OH --OCH.sub.3 H
1480 --CH.sub.2--CH.sub.2--O--CH.sub.2--CH.sub.2-- H --OCH.sub.3 H
--OCH.sub.3 1481 --CH.sub.2--CH.sub.2--O--CH.sub.2--CH.sub.2-- H
--SCH.sub.3 H H 1482 --CH.sub.2--CH.sub.2--O--CH.sub.2--CH.sub.2--
H --OCH.sub.3 H H 1483 --CH.sub.2--CH.sub.2--O--CH.sub.2--CH.sub.2-
-- H --OCH.sub.3 --OCH.sub.3 --OCH.sub.3 1484
--CH.sub.2--CH.sub.2--O--CH.sub.2--CH.sub.2-- H --OH --OCH.sub.3
--OCH.sub.3 1485 --CH.sub.2--CH.sub.2--O--CH.sub.2--CH.sub.2-- H H
--SCH.sub.3 H 1486 --CH.sub.2--CH.sub.2--O--CH.sub.2--CH.sub.2-- H
H --OCH.sub.3 H 1487 --CH.sub.2--CH.sub.2--O--CH.sub.2--CH.sub.2--
H --OCH.sub.3 --OH H 1488 --CH.sub.2--CH.sub.2--O--CH.sub.2--CH.su-
b.2-- --OCH.sub.3 --CH.sub.3 H H 1489
--CH.sub.2--CH.sub.2--O--CH.s- ub.2--CH.sub.2-- H
--CH.sub.2--CH.sub.3 H H 1490
--CH.sub.2--CH.sub.2--O--CH.sub.2--CH.sub.2-- --OCH.sub.3
--CH(CH.sub.3).sub.2 H H 1491 --CH.sub.2--CH.sub.2--O--CH.sub.2--C-
H.sub.2-- H --C.sub.3H.sub.7-n H H 1492
--CH.sub.2--CH.sub.2--O--CH- .sub.2--CH.sub.2-- H
--OCH.sub.2--CH.sub.3 H H 1493
--CH.sub.2--CH.sub.2--O--CH.sub.2--CH.sub.2-- H F H H 1494
--CH.sub.2--CH.sub.2--O--CH.sub.2--CH.sub.2-- H Cl H H 1495
--CH.sub.2--CH.sub.2--O--CH.sub.2--CH.sub.2-- H Br H H 1496
--CH.sub.2--CH.sub.2--O--CH.sub.2--CH.sub.2-- H Cl Cl H 1497
--CH.sub.2--CH.sub.2--O--CH.sub.2--CH.sub.2-- H OH OH OH 1498
--CH.sub.2--CH.sub.2--O--CH.sub.2--CH.sub.2-- Cl Cl H Cl 1499
--CH.sub.2--CH.sub.2--O--CH.sub.2--CH.sub.2-- H --CF.sub.3 H H 1500
--CH.sub.2--CH.sub.2--O--CH.sub.2--CH.sub.2-- H --OCF.sub.3 H H
1501 --CH.sub.2--CH.sub.2--O--CH.sub.2--CH.sub.2-- H
--C.sub.2F.sub.5 H H 1502
--CH.sub.2--CH.sub.2--O--CH.sub.2--CH.sub.2-- H
--C.sub.4H.sub.9-tert H H 1503 --CH.sub.2--CH.sub.2--O--CH.sub.2---
CH.sub.2-- H --OC.sub.3H.sub.7-i H H 1504
--CH.sub.2--CH.sub.2--O--- CH.sub.2--CH.sub.2-- H --SO--CH.sub.3 H
H 1505 --CH.sub.2--CH.sub.2--O--CH.sub.2--CH.sub.2-- H
--SO.sub.2--CH.sub.3 H H 1506
--CH.sub.2--CH.sub.2--O--CH.sub.2--CH.sub.2-- H
--NH--CH.sub.2--CH.sub.3 H H 1507 --CH.sub.2--CH.sub.2--O--CH.sub.-
2--CH.sub.2-- H --O--CH.sub.2--CH.dbd.CH.sub.2 H H 1508
--CH.sub.2--CH.sub.2--O--CH.sub.2--CH.sub.2-- H
--O--CH.sub.2--C.dbd.CH H H 1509
--CH.sub.2--CH.sub.2--O--CH.sub.2--CH.sub.2-- H
--NH--CH.sub.2--CH.sub.2--NH--CH.sub.3 H H 1510
--CH.sub.2--CH.sub.2--O--CH.sub.2--CH.sub.2-- H
--SO.sub.2--C.sub.2H.sub.- 5 H H 1511
--CH.sub.2--CH.sub.2--O--CH.sub.2--CH.sub.2-- H
--SO.sub.2--CH.sub.3 Cl H 1512 --CH.sub.2--CH.sub.2--O--CH.sub.2---
CH.sub.2-- H --CH.sub.2--CN H H 1513
--CH.sub.2--CH.sub.2--O--CH.su- b.2--CH.sub.2-- H
--CH--(CH.sub.3)--CN H H 1514
--CH.sub.2--CH.sub.2--O--CH.sub.2--CH.sub.2-- H
--C(CH.sub.3).sub.2--CN H H 1515
--CH.sub.2--CH.sub.2--O--CH.sub.2--CH.sub.2-- H
--CH--(C.sub.2H.sub.5)--CN H H 1516 --CH.sub.2--CH.sub.2--O--CH.su-
b.2--CH.sub.2-- H --C(C.sub.2H.sub.5).sub.2--CN H H 1517
--CH.sub.2--CH.sub.2--O--CH.sub.2--CH.sub.2-- H
--CH.sub.2--CH.sub.2--CN H H 1518
--CH.sub.2--CH.sub.2--O--CH.sub.2--CH.sub.2-- H
--CH(CH.sub.3)--CH.sub.2--CN H H 1519 --CH.sub.2--CH.sub.2--O--CH.-
sub.2--CH.sub.2-- H --CH.sub.2--CO.sub.2--CH.sub.3 H H 1520
--CH.sub.2--CH.sub.2--O--CH.sub.2--CH.sub.2-- H
--CH(CH.sub.3)--CO.sub.2-- -CH.sub.3 H H 1521
--CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.sub.2--CH.- sub.2-- H
--CH.sub.2--O--CH.sub.3 H H 1522 --CH.sub.2--CH.sub.2--N(-
CH.sub.3)--CH.sub.2--CH.sub.2-- H --NH--CO--CH.sub.3 H H 1523
--CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.sub.2--CH.sub.2-- H
--CH.sub.2--NH--CO--CH.sub.3 H H 1524 --CH.sub.2--CH.sub.2--N(CH.s-
ub.3)--CH.sub.2--CH.sub.2-- H --CH(CH.sub.3)--NH--CO--CH.sub.3 H H
1525 --CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.sub.2--CH.sub.2-- H
--C(CH.sub.3).sub.2--NH--CO--CH.sub.3 H H 1526
--CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.sub.2--CH.sub.2-- H
--CH(CH.sub.3)--O--CH.sub.3 H H 1527 --CH.sub.2--CH.sub.2--N(CH.su-
b.3)--CH.sub.2--CH.sub.2-- H --C(CH.sub.3).sub.2--O--CH.sub.3 H H
1528 --CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.sub.2--CH.sub.2-- H
--CH(CH.sub.3)--O--CO--CH.sub.3 H H 1529 --CH.sub.2--CH.sub.2--N(C-
H.sub.3)--CH.sub.2--CH.sub.2-- H --CH.sub.2--O--CO--CH.sub.3 H H
1530 --CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.sub.2--CH.sub.2-- H
--C(CH.sub.3).sub.2--O--CO--CH.sub.3 H H 1531
--CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.sub.2--CH.sub.2-- H
--CH.sub.2--CH.sub.2--O--H H H 1532 --CH.sub.2--CH.sub.2--N(CH.sub-
.3)--CH.sub.2--CH.sub.2-- H --CH.sub.2--CH.sub.2--O--CH.sub.3 H H
1533 --CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.sub.2--CH.sub.2-- H 277
H H 1534 --CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.sub.2--CH.- sub.2--
H 278 H H 1535 --CH.sub.2--CH.sub.2--N(CH.sub.3)---
CH.sub.2--CH.sub.2-- H 279 H H 1536
--CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.sub.2--CH.sub.2-- H 280 H H
1537 --CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.sub.2--CH.sub.2-- H 281
H H 1538 --CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.sub.2-- -CH.sub.2--
H 282 H H 1539 --CH.sub.2--CH.sub.2--N(CH.sub.-
3)--CH.sub.2--CH.sub.2-- H 283 H H 1540
--CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.sub.2--CH.sub.2-- H 284 H H
1541 --CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.sub.2--CH.sub.2-- H 285
H H 1543 --CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.sub.2-- -CH.sub.2--
H 286 H H 1544 --CH.sub.2--CH.sub.2--N(CH.sub.-
3)--CH.sub.2--CH.sub.2-- H 287 H H 1545
--CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.sub.2--CH.sub.2-- H 288 H H
1546 --CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.sub.2--CH.sub.2-- H H H
H 1547 --CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.sub.2--CH.sub.2-- H CN
H H 1548 --CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.sub.2--CH.sub.2-- -
H --C(CH.sub.3).sub.2--OH H H 1549 --CH.sub.2--CH.sub.2--N(CH.sub-
.3)--CH.sub.2--CH.sub.2-- H --CH.sub.2--OH H H 1550
--CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.sub.2--CH.sub.2-- H
--CO--CH.sub.3 H H 1551
--CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.sub.2--CH.sub.2-- H
--C(.dbd.NOH)--CH.sub.3 H H 1552 --CH.sub.2--CH.sub.2--N(CH.sub.3)-
--CH.sub.2--CH.sub.2-- H --CH(OH)--CH.sub.3 H H 1553
--CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.sub.2--CH.sub.2-- H (3)
--CO--O--CH.sub.2-- (4) H 1554 --CH.sub.2--CH.sub.2--N(CH.sub.3)--
-CH.sub.2--CH.sub.2-- H --CH.sub.2--O--CO--CH.sub.3 H H 1555
--CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.sub.2--CH.sub.2-- H
--C(.dbd.NO--CH.sub.3)--CH.sub.3 H H 1556 --CH.sub.2--CH.sub.2--N(-
CH.sub.3)--CH.sub.2--CH.sub.2-- H --CO--O--CH.sub.3 H H 1557
--CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.sub.2--CH.sub.2-- H
--NH--CO--C.sub.3H.sub.5-cycl. H H 1558 --CH.sub.2--CH.sub.2--N(CH-
.sub.3)--CH.sub.2--CH.sub.2-- H --CO--CH.sub.3 Cl H 1559
--CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.sub.2--CH.sub.2-- H --OH H H
1560 --CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.sub.2--CH.sub.2-- H --OH
--OCH.sub.3 H 1561 --CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.sub.2--CH-
.sub.2-- H --OCH.sub.3 H --OCH.sub.3 1562
--CH.sub.2--CH.sub.2--N(C-
H.sub.3)--CH.sub.2--CH.sub.2-- H --SCH.sub.3 H H 1563
--CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.sub.2--CH.sub.2-- H
--OCH.sub.3 H H 1564
--CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.sub.2--CH.sub.2-- H
--OCH.sub.3 --OCH.sub.3 --OCH.sub.3 1565 --CH.sub.2--CH.sub.2--N(C-
H.sub.3)--CH.sub.2--CH.sub.2-- H --OH --OCH.sub.3 --OCH.sub.3 1566
--CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.sub.2--CH.sub.2-- H H
--SCH.sub.3 H 1567
--CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.sub.2--CH.sub.2-- H H
--OCH.sub.3 H 1568 --CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.sub.2--CH-
.sub.2-- H --OCH.sub.3 --OH H 1569
--CH.sub.2--CH.sub.2--N(CH.sub.3- )--CH.sub.2--CH.sub.2--
--OCH.sub.3 --CH.sub.3 H H 1570
--CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.sub.2--CH.sub.2-- H
--CH.sub.2--CH.sub.3 H H 1571 --CH.sub.2--CH.sub.2--N(CH.sub.3)--C-
H.sub.2--CH.sub.2-- --OCH.sub.3 --CH(CH.sub.3).sub.2 H H 1572
--CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.sub.2--CH.sub.2-- H
--C.sub.3H.sub.7-n H H 1573 --CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.-
sub.2--CH.sub.2-- H --OCH.sub.2--CH.sub.3 H H 1574
--CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.sub.2--CH.sub.2-- H F H H
1575 --CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.sub.2--CH.sub.2-- H Cl H
H 1576 --CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.sub.2--CH.sub.2-- H Br
H H 1577 --CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.sub.2--CH.sub.2-- H
Cl Cl H 1578
--CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.sub.2--CH.sub.2-- H OH OH OH
1579 --CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.sub.2--CH.su- b.2-- Cl
Cl H Cl 1580 --CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.sub.2---
CH.sub.2-- H --CF.sub.3 H H 1581
--CH.sub.2--CH.sub.2--N(CH.sub.3)-- -CH.sub.2--CH.sub.2-- H
--OCF.sub.3 H H 1582
--CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.sub.2--CH.sub.2-- H
--C.sub.2F.sub.5 H H 1583 --CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.su-
b.2--CH.sub.2-- H --C.sub.4H.sub.9-tert H H 1584
--CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.sub.2--CH.sub.2-- H
--OC.sub.3H.sub.7-i H H 1585 --CH.sub.2--CH.sub.2--N(CH.sub.3)--CH-
.sub.2--CH.sub.2-- H --SO--CH.sub.3 H H 1586
--CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.sub.2--CH.sub.2-- H
--SO.sub.2--CH.sub.3 H H 1587 --CH.sub.2--CH.sub.2--N(CH.sub.3)--C-
H.sub.2--CH.sub.2-- H --NH--CH.sub.2--CH.sub.3 H H 1588
--CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.sub.2--CH.sub.2-- H
--O--CH.sub.2--CH.dbd.CH.sub.2 H H 1589 --CH.sub.2--CH.sub.2--N(CH-
.sub.3)--CH.sub.2--CH.sub.2-- H --O--CH.sub.2--C.dbd.CH H H 1590
--CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.sub.2--CH.sub.2-- H
--NH--CH.sub.2--CH.sub.2--NH--CH.sub.3 H H 1591
--CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.sub.2--CH.sub.2-- H
--SO.sub.2--C.sub.2H.sub.5 H H 1592 --CH.sub.2--CH.sub.2--N(CH.sub-
.3)--CH.sub.2--CH.sub.2-- H --SO.sub.2--CH.sub.3 Cl H 1593
--CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.sub.2--CH.sub.2-- H
--CH.sub.2--CN H H 1594
--CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.sub.2--CH.sub.2-- H
--CH--(CH.sub.3)--CN H H 1595 --CH.sub.2--CH.sub.2--N(CH.sub.3)--C-
H.sub.2--CH.sub.2-- H --C(CH.sub.3).sub.2--CN H H 1596
--CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.sub.2--CH.sub.2-- H
--CH--(C.sub.2H.sub.5)--CN H H 1597 --CH.sub.2--CH.sub.2--N(CH.sub-
.3)--CH.sub.2--CH.sub.2-- H --C(C.sub.2H.sub.5).sub.2--CN H H 1598
--CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.sub.2--CH.sub.2-- H
--CH.sub.2--CH.sub.2--CN H H 1599 --CH.sub.2--CH.sub.2--N(CH.sub.3-
)--CH.sub.2--CH.sub.2-- H --CH(CH.sub.3)--CH.sub.2--CN H H 1600
--CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.sub.2--CH.sub.2-- H
--CH.sub.2--CO.sub.2--CH.sub.3 H H 1601 --CH.sub.2--CH.sub.2--N(CH-
.sub.3)--CH.sub.2--CH.sub.2-- H --CH(CH.sub.3)--CO.sub.2--CH.sub.3
H H
[0246] For the following example compounds physico-chemical data
have been obtained and are displayed in order to illustrate the
working of the present invention, including the outlined methods of
synthesis. The number of given data may not be interpreted as a
limitation of the invention.
12 TABLE B Comp. Melting point [OC] or No. 1H-NMR [.delta. in ppm]
01.0025 244-245 01.0026 260-261 01.0027 219-220 01.0028 214-215
01.0029 228-229 01.0030 >260 01.0031 216-217 01.0032 >260
01.0034 237-238 01.0035 223-225 01.0038 133-234 01.0039 244-245
01.0042 115-117 01.0052 243-245 01.0169 244-245 01.0307 >260
01.0315 235-236 01.0377 >260 01.0448 188-189 01.0588 255-256
01.0658 206-207 01.0729 >260 01.0869 196-197 01.0940 230 01.1013
>260 01.1083 178-179 01.1465 233-234 01.1546 239-240 02.0026
236-238 02.0027 252-253 02.0028 >260 02.0031 260-261 02.0038
256-258 02.0041 238-240 02.0042 223-225 02.0052 208-210 02.0054
>260 02.0058 >260 02.0059 >260 02.0061 239-240 02.0063
222-223 02.0123 >260 02.0124 >260 02.0193 >260 02.1130
259-260 03.0025 >260 03.0026 >260 03.0029 255-256 03.0035
241.242 03.0236 224.227 03.0242 88-91 04.0035 236-237 06.0025
>260 06.0026 >260 06.0029 >260 06.0035 249-250 07.0025
212-213 07.0026 234-235 07.0029 198-200 10.0029 228-229 10.0518
90-92
[0247] In the following, examples of test systems in plant
protection are provided which can demonstrate the efficiency of the
compounds of the formula I (designated as ,,active ingredient "or
,,test compounds"):
Biological Examples
Example B-1
Effect Against Puccinia graminis on Wheat (Brownrust on Wheat)
[0248] a) Residual Protective Activity
[0249] 1 week old wheat plants cv. Arina are treated with the
formulated test-compound (0.02% active substance) in a spray
chamber. Two days after application wheat plants are inoculated by
spraying a spore suspension (1.times.10.sup.5 ureidospores/ml) on
the test plants. After an incubation period of 1 day at +20.degree.
C. and 95% relative atmospheric humidity (r. h.) plants are kept
for 9 days at +20.degree. C. and 60% r.h. in a greenhouse. The
disease incidence is assessed 10 days after inoculation.
[0250] Compounds of Tables 1 to 10 Show Good Activity in this
Test.
[0251] b) Systemic Activity
[0252] An aqueous spray liquor prepared from the formulated test
compound (0.002% active substance, based on the volume of soil) is
poured onto wheat plants 5 days after sowing. Care is taken that
the spray liquor does not come into contact with the above-ground
parts of the plant. 48 hours later, the plants are inoculated with
a spore suspension of the fungus. After an incubation period of 48
hours (95 to 100% r.h. at +20.degree. C.), the plants are placed in
a greenhouse at +20.degree. C. 12 days after infection, the disease
incidence is evaluated.
[0253] Compounds of Tables 1 to 10 Show Good Activity in this
Test.
Example B-2
Effect Against Phytophthora infestans on Tomatoes (Late Blight on
Potato)
[0254] a) Residual Protective Activity
[0255] 3 week old tomato plants cv. Roter Gnom are treated with the
formulated test compound (0.02% active substance) in a spray
chamber. Two day after application the plants are inoculated by
spraying a sporangia suspension (2.times.10.sup.4 sporangia/ml) on
the test plants. After an incubation period of 4 days at
+18.degree. C. and 95% r.h. in a growth chamber the disease
incidence is assessed.
[0256] Compounds of Tables 1 to 10 Show Good Activity in this
Test.
[0257] At the indicated concentration compounds 01.0025, 01.0028,
01.0031, 01.0307, 01.0315, 01.0729, 02.0027, 02.0028, 02.0031,
02.0038, 10.0029, and 10.0518 exhibited over 70% control of the
fungal infection in this test.
[0258] b) Systemic Activity
[0259] An aqueous suspension prepared from the formulated test
compound (0.002% active substance, based on the volume of soil) is
poured onto tomato plants which have been cultivated for three
weeks. Care is taken that the spray liquor does not come into
contact with the above-ground parts of the plant. 48 hours later,
the plants are inoculated with a sporangia suspension of the
fungus. Evaluation of the disease incidence takes place 5 days
after infection, during which period conditions of 90 to 100% r.h.
and +20.degree. C. are maintained.
[0260] Compounds of Tables 1 to 10 Show Good Activity in this
Test.
[0261] At the indicated concentration compounds 01.0025, 01.0028,
01.0031, 01.0307, 01.0315, 01.0729, 02.0027, 02.0028, 02.0031,
02.0038, 10.0029, and 10.0518 exhibited over 70% control of the
fungal infection in this test.
Example B-3
Effect Against Phytophthora infestans/Potato (Late Blight on
Potato)
[0262] 5 week old potato plants cv. Bintje are treated with the
formulated test compound (0.02% active substance) in a spray
chamber. Two days after application the plants are inoculated by
spraying a sporangia suspension (1.4.times.10.sup.5 sporangia/ml)
on the test plants. After an incubation period of 4 days at
+18.degree. C. and 95% r. h. in a growth chamber the disease
incidence is assessed.
[0263] Compounds of Tables 1 to 10 Show Good Activity in this
Test.
[0264] At the indicated concentration compounds 01.0025, 01.0028,
01.0031, 01.0307, 01.0315, 01.0729, 02.0027, 02.0028, 02.0031,
02.0038, 10.0029, and 10.0518 exhibited over 70% control of the
fungal infection in this test.
Example B-4
Effect Against Plasmopara viticola on Grapevine (Grape Downy
Mildew)
[0265] 5 week old grape seedlings cv. Gutedel are treated with the
formulated test compound (0.02% active substance) in a spray
chamber. One day after application grape plants are inoculated by
spraying a sporangia suspension (4.times.10.sup.4 sporangia/ml) on
the lower leaf side of the test plants. After an incubation period
of 6 days at +22.degree. C. and 95% r. h. in a greenhouse the
disease incidence is assessed.
[0266] Compounds of Tables 1 to 10 Show Good Activity in this
Test.
[0267] At the indicated concentration compounds 01.0025, 01.0027,
01.0028, 01.0030, 01.0031, 01.0034, 01.0042, 01.0169, 01.0658,
01.0729, 01.0869, 02.0027, 02.0028, 02.0031, 02.0038, 10.0029 and
10.0518 exhibited over 70% control of the fungal infection in this
test.
Example B-5
Residual Protective Activity Against Venturia inaequalis on Apples
(Scab on Apple)
[0268] 4 week old apple seedlings cv. McIntosh are treated with the
formulated test compound (0.02% active substance) in a spray
chamber. One day after application apple plants are inoculated by
spraying a spore suspension (4.times.10.sup.5 conidia/ml) on the
test plants. After an incubation period of 4 days at +21.degree. C.
and 95% r. h. the plants are placed for 4 days at +21.degree. C.
and 60% r. h. in a greenhouse. After another 4 day incubation
period at +21.degree. C. and 95% r. h. the disease incidence is
assessed.
[0269] Compounds of Tables 1 to 10 Show Good Activity in this
Test.
Example B-6
Effect Against Erysiphe graminis on Barley (Powdery Mildew on
Barley)
[0270] a) Residual Protective Activity
[0271] Barley plants of approximately 8 cm height are sprayed to
drip point with an aqueous spray liquor prepared from wettable
powder of the active ingredient (0.02% active substance), and
dusted 3 to 4 hours later with conidia of the fungus. The infected
plants are placed in a greenhouse at +22.degree. C. 12 days after
infection, the fungal attack is evaluated.
[0272] Compounds of Tables 1 to 10 Show Good Activity in this
Test.
[0273] b) Systemic Activity
[0274] An aqueous spray liquor prepared from the formulated test
compound (0.002% active substance, based on the volume of soil) is
poured onto barley plants of approximately 8 cm height. Care is
taken that the spray liquor does not come into contact with the
above-ground parts of the plant. 48 hours later, the plants are
dusted with conidia of the fungus. The infected plants are placed
in a greenhouse at +22.degree. C. 12 days after infection, the
disease incidence is evaluated.
[0275] Compounds of Tables 1 to 10 Show Good Activity in this
Test.
Example B-7
Botrytis cinerea/Grape (botrytis on Grapes)
[0276] 5 week old grape seedlings cv. Gutedel are treated with the
formulated test compound (0.02% active substance) in a spray
chamber. Two days after application grape plants are inoculated by
spraying a spore suspension (1.times.10.sup.6 conidia/ml) on the
test plants. After an incubation period of 4 days at +21.degree. C.
and 95% r. h. in a greenhouse the disease incidence is
assessed.
[0277] Compounds of Tables 1 to 10 Show Good Activity in this
Test.
[0278] At the indicated concentration compound 01.0042 exhibited
over 70% control of the fungal infection in this test.
Example B-8
Effect Against Botrytis cinerea/Tomato (botrytis on Tomatoes)
[0279] 4 week old tomato plants cv. Roter Gnom are treated with the
formulated test compound 0.02% active substance) in a spray
chamber. Two days after application tomato plants are inoculated by
spraying a spore suspension (1.times.10.sup.5 conidia/ml) on the
test plants. After an incubation period of 4 days at +20.degree. C.
and 95% r. h. in a greenhouse the disease incidence is
assessed.
[0280] Compounds of Tables 1 to 10 Show Good Activity in this
Test.
[0281] At the indicated concentration compound 01.0042 exhibited
over 70% control of the fungal infection in this test.
Example B-9
Effect Against Pyricularia oryzae/Rice (Rice Blast)
[0282] 3 week old rice plants cv. Sasanishiki are treated with the
formulated test compound (0.02% active substance) in a spray
chamber. Two days after application rice plants are inoculated by
spraying a spore suspension (1.times.10.sup.5 conidia/ml) on the
test plants. After an incubation period of 6 days at +25.degree. C.
and 95% r. h. the disease incidence is assessed.
[0283] Compounds of Tables 1 to 10 Show Good Activity in this
Test.
Example B-10
Effect Against Pyrenophora teres (Helminthosporium)/Barley (Net
Blotch on Barley)
[0284] 1 week old barley plants cv. Regina are treated with a
formulated test compound (0.02% active substance) in a spray
chamber. Two days after application barley plants are inoculated by
spraying a spore suspension (3.times.10.sup.4 conidia/ml) on the
test plants. After an incubation period of 2 days at +20.degree. C.
and 95% r.h. plants are kept for 2 days at +20.degree. C. and 60%
r.h. in a greenhouse. The disease incidence is assessed 4 days
after inoculation.
[0285] Compounds of Tables 1 to 10 Show Good Activity in this
Test.
[0286] At the indicated concentration compound 01.0028 exhibited
over 70% control of the fungal infection in this test.
Example B-11
Effect Against Fusarium culmorum/Wheat (Fusarium Head Blight on
Wheat)
[0287] A conidia suspension of F. culmorum (7.times.10.sup.5
conidia/ml) is mixed with the formulated test compound (0.002%
active substance).. The mixture is applied into a pouch which has
been equipped before with a filter paper. After the application
wheat seeds (cv. Orestis) are sown into the upper fault of the
filter paper. The prepared pouches are then incubated for 11 days
at approx. +10.degree. C. to +18.degree. C. and a relative humidity
of 100% with a light period of 14 hours. The evaluation is made by
assessing the degree of disease occurrence in the form of brown
lesions on the roots.
[0288] Compounds of Tables 1 to 10 Show Good Activity in this
Test.
Example B-12
Effect Against Septoria nodorum/Wheat (Septoria Leaf Spot on
Wheat)
[0289] 1 week old wheat plants cv. Arina are treated with a
formulated test compound (0.02% active substance) in a spray
chamber. One day after application wheat plants are inoculated by
spraying a spore suspension (5.times.10.sup.5 conidia/ml) on the
test plants. After an incubation period of 1 day at +20.degree. C.
and 95% r.h. plants are kept for 10 days at +20.degree. C. and 60%
r.h. in a greenhouse. The disease incidence is assessed 11 days
after inoculation.
[0290] Compounds of Tables 1 to 10 Show Good Activity in this
Test.
* * * * *